Nogueira, Raul G.

Background Relationships between occlusive clot histopathology, baseline characteristics, imaging findings, revascularization rates, and clinical outcomes of stroke patients with large vessel occlusion (LVO) are not well understood. This study will assess the real-world experience on the efficacy and safety of using the EmboTrap device as the first approach in LVO patients and explore the associations between clot histological characteristics, imaging and clinical findings, revascularization rates, and clinical outcomes. Methods Prospective, global, multicenter, single-arm, imaging core laboratory, and clot analysis central laboratory observational registry. Adult patients (>18 years) with LVO, treated with EmboTrap as the first attempted device, will be eligible for study participation. Results Up to 1000 subjects at 50 international sites may be enrolled. Occlusive clots will be collected from at least 500 subjects. Independent central and imaging core laboratories will perform clot analysis and image adjudication. Statistical analysis will assess the association between imaging and clinical findings, clot characteristics, subject comorbidities, revascularization, and clinical outcomes. Study endpoints are functional independence (modified Rankin Scale score ≤2 at 90 days), expanded Thrombolysis In Cerebral Infarction (eTICI) score ≥2b50 rate, first-pass effect, number of passes, embolization into new territory, symptomatic intracranial hemorrhage, and 90-day mortality. Conclusions The EXCELLENT registry will provide reproducible effectiveness and safety data of EmboTrap for its use for mechanical thrombectomy. Additionally, the study will characterize the blood clots retrieved during mechanical thrombectomy with respect to their composition and histopathological analysis and potential correlations with clinical and imaging findings. Trial registration number NCT03685578 .

There has been growing interest and insight into the histological composition of retrieved stroke emboli. One of the main focuses of the stroke clot analysis literature has been the implications of clot composition on mechanical thrombectomy procedures. However, the holy grail of clot analysis may not be in the field of clot–device interaction, but rather, in understanding mechanisms of fibrinolysis resistance. The mechanisms underlying the low response to fibrinolytic therapy, even with the newer, more powerful agents, remain poorly understood. While factors such as embolus size, location and collateral status influence alteplase delivery and recanalisation rates; compositional analyses focused on histological and ultrastructural characteristics offer unique insights into mechanisms of alteplase resistance. In this review, we strive to provide comprehensive review of current knowledge on clot composition and ultrastructural analyses that help explain resistance to fibrinolysis.

Background: We performed a multicenter prospective clinical registry across 11 centers to study the association between histopathological characteristics of retrieved clots and imaging, stroke etiology and clinical outcomes. Materials and Methods: Following IRB approval at the 11 centers, patients were enrolled in the STRIP registry. All retrieved emboli were sent for histopathological analysis with H&E and MSB staining. Demographic variables, comorbidities, stroke etiology, imaging findings and procedural details were collected for each case. We studied the association between clot histopathology and imaging findings, stroke etiology and and revascularization outcomes. Student’s t-test was used for continuous variables and chi-squared testing for categorical variables. Results: To date, 1022 patients have been included. There was a significant correlation between platelet rich clots and the absence of hyperdensity on non-contrast CT [p=0.321, p=0.003) and a significant inverse correlation between the percentage of platelets and mean HU on NCCT (p=-0.243, p=0.025). The proportion of platelet-rich clots (55.0% versus 21.2%, p=0.005) and the percentage of platelet content (22.1% versus 13.9%, p=0.03) was significantly higher in patient with large artery atherosclerosis compared to those with a cardioembolic etiology. There was no correlation between RBC density, WBC density, fibrin density or platelet density and revascularization outcomes with stent-retrievers. However, we have found that with aspiration alone, patients with platelet rich clots are less likely to be fully revascularized (i.e. TICI 2c/3) than non-platelet rich clots (OR=0.36, 95%CI=0.12-0.81, P<.0001). Meanwhile, patients with RBC rich clots are more likely to be completely revascularized with aspiration alone than those with RBC poor clots (OR=2.71, 95%CI=1.25-3.24, P=0.02). Conclusions: Interim analysis of the STRIP registry suggests that the platelet content of a clot may be the most revealing factor in determining a clot’s etiology, imaging features and revascularization outcome. Platelet rich clots are less dense on NCCT, are associated with a large artery atherosclerosis source and are less likely to be completely revascularized with aspiration alone.

Background and Purpose: Field Assessment Stroke Triage for Emergency Destination (FAST-ED) scale is a helpful tool to triage patients with stroke in the field. However, data on its reliability in the prehospital setting are lacking. We aim to test the reliability of FAST-ED scale when used by paramedics in a mobile stroke unit covering a metropolitan area. Methods: As part of standard operating mobile stroke unit procedures, paramedics initially evaluated patients. If the event characterized a stroke alert, the FAST-ED score was determined by the paramedic upon patient contact (in-person) and then independently by a vascular neurologist (VN) immediately after paramedic evaluation (remotely/telemedicine). This allowed testing of the interrater agreement of the FAST-ED scoring performance between on-site prehospital providers and remotely located VN. Results: Of a total of 238 patients transported in the first 15 months of the mobile stroke unit’s activity, 173 were included in this study. Median age was 63 (interquartile range, 55.5–75) years and 52.6% were females. A final diagnosis of ischemic stroke was made in 71 (41%), transient ischemic attack in 26 (15%), intracranial hemorrhage in 15 (9%), whereas 61 (35%) patients were stroke mimics. The FAST-ED scores matched perfectly among paramedics and VN in 97 (56%) instances, while there was 0 to 1-point difference in 158 (91.3%), 0 to 2-point difference in 171 (98.8%), and 3 or more point difference in 2 (1.1%) patients. The intraclass correlation between VN and paramedic FAST-ED scores showed excellent reliability, intraclass correlation coefficient 0.94 (95% CI, 0.92–0.96; P <0.001). When VN recorded FAST-ED score ≥3, paramedics also scored FAST-ED≥3 in majority of instances (63/71 patients; 87.5%). A large vessel occlusion was identified in 16 (9.2%) patients; 13 occlusions were identified with a FAST-ED≥3 while 3 were missed. All of the latter patients had National Institutes of Health Stroke Scale score ≤5. Conclusions: We demonstrate excellent reliability of FAST-ED scale performed by paramedics when compared with VN, indicating that it can be accurately performed by paramedics in the prehospital setting.

Background Several animal studies have demonstrated that mechanical thrombectomy (MT) for acute ischemic stroke (AIS) may cause vessel wall injury (VWI). However, the histological changes in human cerebral arteries following MT are difficult to determine. Objective To investigate the occurrence of VWI during MT by histological and immunohistochemical evaluation of AIS clots. Methods As part of the multicenter STRIP registry, 277 clots from 237 patients were analyzed using Martius Scarlett Blue stain and immunohistochemistry for CD34 (endothelial cells) and smooth muscle actin (smooth muscle cells). Results MT devices used were aspiration catheters (100 cases), stentriever (101 cases), and both (36 cases). VWI was found in 33/277 clots (12%). There was no significant correlation between VWI and MT device. The degree of damage varied from grade I (mild intimal damage, 24 clots), to grade II (relevant intimal and subintimal damage, 3 clots), and III (severe injury, 6 clots). VWI clots contained significantly more erythrocytes (p=0.006*) and less platelets/other (p=0.005*) than non-VWI clots suggesting soft thrombus material. Thrombolysis correlated with a lower rate of VWI (p=0.04*). VWI cases showed a significantly higher number of passes (2 [1–4] vs 1 [1–3], p=0.028*) and poorer recanalization outcome (p=0.01*) than cases without VWI. Conclusions Histological markers of VWI were present in 12% of AIS thrombi, suggesting that VWI might be related to MT. VWI was associated with soft thrombus consistency, higher number of passes and poorer revascularization outcome. There was no significant correlation between VWI and MT device.

Background and aim Mechanical thrombectomy (MT) for large vessel occlusion often requires multiple passes to retrieve the entire thrombus load. In this multi-institutional study we sought to examine the composition of thrombus fragments retrieved with each pass during MT. Methods Patients who required multiple passes during thrombectomy were included. Histopathological evaluation of thrombus fragments retrieved from each pass was performed using Martius Scarlet Blue staining and the composition of each thrombus component including RBC, fibrin and platelet was determined using image analysis software. Results 154 patients underwent MT and 868 passes was performed which resulted in 263 thrombus fragments retrieval. The analysis of thrombus components per pass showed higher RBC, lower fibrin and platelet composition in the pass 1 and 2 when compared to pass 3 and passes 4 or more combined (P values <0.05). There were no significant differences between thrombus fragments retrieved in pass 1 and pass 2 in terms of RBC, WBC, fibrin, and platelet composition (P values >0.05). Similarly, when each composition of thrombus fragments retrieved in pass 3 and passes 4 or more combined were compared with each other, no significant difference was noted (P values >0.05). Conclusion Our findings confirm that thrombus fragments retrieved with each pass differed significantly in histological content. Fragments in the first passes were associated with lower fibrin and platelet composition compared to fragments retrieved in passes three and four or higher. Also, thrombus fragments retrieved after failed pass were associated with higher fibrin and platelet components.

Introduction: Evidence regarding the optimal acute antiplatelet strategies in emergent endovascular therapies is scarce, and practices varies institutionally. Ticagrelor, a P2Y3B inhibitor with a lower incidence of resistance, may be effective in achieving rapid platelet inhibition. We explore the safety and efficacy of emergent Ticagrelor use in patient undergoing neurointerventions. Methods: We reviewed our database for all consecutive patients from 2016 to 2019 who received emergent administration of Ticagrelor (within 30 minutes before or after) for neuro-interventional procedures. The primary outcome measure was the incidence of major systemic hemorrhages including symptomatic intracranial hemorrhage as well as intraprocedural and post-procedural thrombotic events. Results: 81 patients were analyzed (Mean age 62±11, 70% male, 73 undergoing interventions for ischemic strokes, 8 aneurysm patients undergoing embolization). Twenty (24.7%) patients received Ticagrelor pre-puncture, 28 (35%) during and 33 (41%) after closure. Median PRU achieved in 43 patients after excluding for concomitant use of GPIIbIIIa use was 54 [36-111]. Major bleeding occurred in 7/81 patients (9.2%) - 4 gastrointestinal bleeding and 3 symptomatic ICH. Eleven (14%) patients experienced intraprocedural occlusions. Five (6.2%) cases were complicated by post-procedural occlusions while on Ticagrelor, two of which were asymptomatic. Pre-procedural Ticagrelor was associated with less frequent administration of subsequent GPIIbIIIa (OR = 0.15, 95% CI (0.03-0.64), p=0.01), as well as shorter procedure duration (Spearman’s rho 0.409, p =0.001). The use of GPIIbIIIa plus Ticagrelor was associated with increased bleeding complications (0% vs. 14%; p =0.04) than in patients receiving Ticagrelor only. Bleeding was an independently predictive risk factor for death by 3 months (OR 7.18, 95% CI (1.33-38.8, p=0.02 or 43% vs. 9.5%; p=0.04) Conclusion: Early and emergent use of Ticagrelor, prior to endovascular procedure as early as within 30 minutes, may obviate the need for administration of GPIIbIIIa. Combined use of GPIIbIIa antithrombotics with Ticagrelor was associated with hemorrhagic complications, which could contribute to increased mortality.

Background and Purpose: The hypoperfusion intensity ratio (HIR) is a perfusion-weighted imaging parameter defined as the ratio of Tmax>10 seconds : Tmax>6 seconds volume and is believed to be reflective of collateral strength and consequently influence infarct growth. We sought to assess the utility of the HIR in predicting infarct growth in patients undergoing thrombectomy at a comprehensive stroke center (CSC). Methods: Consecutive acute ischemic stroke patients transferred to our CSC from 09/2010-11/2018 were identified and included if the following criteria were met: 1)computed tomography perfusion (CTP) imaging enabling assessment of baseline ischemic core volume and HIR 2) follow-up neuroimaging for assessment of final infarct volumes and 3)modified Thrombolysis In Cerebral Infarction scale (mTICI) 2c status or greater post-thrombectomy. Infarct growth rate (IGR) was calculated as the difference between infarct volume on follow-up imaging and the acute DWI lesion volume, divided by time from CTP to reperfusion in hours. Results: 461 patients (median age, 64 [55-75] years, median baseline NIHSS, 16 [12-21]) were eligible for this analysis. HIR poorly correlated with IGR (Spearman’s rho=0.001, p=0.89). An HIR cut-off of 0.5 was not able to discriminate ‘fast progressors’ (IGR>5 mL/hr) (AUC 0.42, sensitivity 40%, specificity 51%), or IGR at thresholds of either 2.5 or 10 mL/hr (AUC 0.44 and 0.49 respectively, with 95% confidence intervals [0.35-0.52] and [0.41-0.57], respectively). Similarly, an HIR of 0.5 only weakly distinguished ‘fast progression’ in patients reperfused beyond 120 min from imaging and patients with early CTP (last known well to CTP<6 hrs) (AUC 0.59, sensitivity 43%, specificity 68% and AUC 0.50, sensitivity 45%, specificity 55%). On multiple regression analysis, HIR was not predictive of infarct growth (regression equation=18.09+8.48x, F=2.46, p=0.11, R 2 =0.13) but was predictive of ‘fast progression’ (OR 0.22, 95% CI [0.09-0.60], p=0.003, pseudo-R 2 =0.16). Conclusions: Though predictive of fast progression, the HIR is a poor discriminator of infarct growth in successfully reperfused thrombectomy patients who undergo perfusion imaging at a CSC, and thus should not be factored into treatment decision-making.

Background and Purpose— Nearly 30% of large vessel occlusion acute ischemic stroke clots are from an unknown source. We assessed histological clot composition in a series of patients with large vessel occlusion and investigated correlations between clot composition and stroke pathogenesis. Methods— As part of the multi-institutional STRIP registry (Stroke Thromboembolism Registry of Imaging and Pathology), consecutive emboli retrieved during mechanical thrombectomy were stained using Martius Scarlett Blue and analyzed using machine learning software. We assessed proportions of red blood cells, fibrin, platelets, and white blood cells. Correlations between clot components and stroke pathogenesis (large artery atherosclerosis, cardioembolism, and stroke of undetermined pathogenesis) were assessed using SPSS22. Results— One hundred five patients were included. The proportion of platelet-rich clots (55.0% versus 21.2%; P =0.005) and percentage of platelet content (22.1±4.2% versus 13.9±14.2%; P =0.03) was significantly higher in the large artery atherosclerosis group compared with the cardioembolic group. The proportion of platelet-rich clots (50.0% versus 21.2%; P =0.024) was also significantly higher in the cryptogenic group compared with cardioembolic cases. Large artery atherosclerosis and cryptogenic cases had a similar proportion of platelet-rich clots (55.0% versus 50.0%; P =0.636). There was no significant difference between stroke pathogenesis and the other major clot components. Conclusions— High platelet content of emboli is associated with a large artery atherosclerosis etiology of large vessel occlusion.