Association between thrombus composition and stroke etiology in the MR CLEAN Registry biobank

Purpose: The composition of thrombi retrieved during endovascular thrombectomy (EVT) in acute ischemic stroke (AIS) due to large vessel occlusion (LVO) may differ depending on their origin. In this study, we investigated the association between thrombus composition and stroke etiology in a large population of patients from the Dutch MR CLEAN Registry treated with EVT in daily clinical practice. Methods: The thrombi of 332 patients with AIS were histologically analyzed for red blood cells (RBC), fibrin/platelets (F/P), and white blood cells (leukocytes) using a machine learning algorithm. Stroke etiology was assessed using the Trial of Org 10,172 in acute stroke treatment (TOAST) classification. Results: The thrombi of cardioembolic origin contained less RBC and more F/P than those of non-cardioembolic origin (25.8% vs 41.2% RBC [p = 0.003] and 67.1% vs 54.5% F/P [p = 0.004]). The likelihood of a non-cardioembolic source of stroke increased with increasing thrombus RBC content (OR 1.02; [95% CI 1.00–1.06] for each percent increase) and decreased with a higher F/P content (OR 1.02; [95% CI 1.00–1.06]). Thrombus composition in patients with a cardioembolic origin and undetermined origin was similar. Conclusion: Thrombus composition is significantly associated with stroke etiology, with an increase in RBC and a decrease in F/P raising the odds for a non-cardioembolic cause. No difference between composition of cardioembolic thrombi and of undetermined origin was seen. This emphasizes the need for more extensive monitoring for arrhythmias and/or extended cardiac analysis in case of an undetermined origin

High-Resolution Imaging of Interaction Between Thrombus and Stent-Retriever in Patients With Acute Ischemic Stroke

BACKGROUND: Currently, acute ischemic stroke is still a leading cause of mortality and morbidity. Approximately 2 years ago, mechanical thrombectomy was proven beneficial as a revolutionary new therapy for stroke in the MR-CLEAN trial (A Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). However, the mechanisms by which the thrombectomy device, or stent-retriever, interacts with the thrombus are largely unknown. A better understanding could lead to improved efficacy of mechanical thrombectomy devices. METHODS AND RESULTS: Seven stent-retrievers with thrombi still entrapped were collected directly after thrombectomy. The stent-retrievers were studied using micro computed tomography, followed by scanning electron microscopy and light microscopy. Two independent observers rated interaction type and thrombus surface structure (porous filamentous or dense) at the interaction sites.A total of 79 interaction sites between thrombus and stent-retriever were categorized. Thrombus-stent-retriever interaction was found to be adhesive (n=44; 56%) or mechanical (n=35; 44%). Adhesive interaction was most frequently observed at interaction sites with a dense surface, compared with interaction sites with a porous filamentous fibrin surface (38/58; 66% versus 6/21; 29%, P=0.011). CONCLUSIONS: The interaction between thrombus and stent-retriever was predominantly adhesive, not mechanical. Adhesive interaction was strongly associated with the presence of a dense thrombus surface without a porous filamentous fibrin network

Mechanical Characterization of Thrombi Retrieved with Endovascular Thrombectomy in Patients with Acute Ischemic Stroke

Background and Purpose: Mechanical properties of thromboemboli play an important role in the efficacy of endovascular thrombectomy (EVT) for acute ischemic stroke. However, very limited data on mechanical properties of human stroke thrombi are available. We aimed to mechanically characterize thrombi retrieved with EVT, and to assess the relationship between thrombus composition and thrombus stiffness. Methods: Forty-one thrombi from 19 patients with acute stroke who underwent EVT between July and October 2019 were mechanically analyzed, directly after EVT. We performed unconfined compression experiments and determined tangent modulus at 75% strain (Et75) as a measure for thrombus stiffness. Thrombi were histologically analyzed for fibrin/platelets, erythrocytes, leukocytes, and platelets, and we assessed the relationship between histological components and Et75with univariable and multivariable linear mixed regression. Results: Median Et75was 560 (interquartile range, 393-1161) kPa. In the multivariable analysis, fibrin/platelets were associated with increased Et75(aβ, 9 [95% CI, 5 to 13]) kPa, erythrocytes were associated with decreased Et75%(aβ,-9 [95% CI,-5 to-13]) kPa. We found no association between leukocytes and Et75. High platelet values were strongly associated with increased Et75(aβ, 56 [95% CI, 38-73]). Conclusions: Fibrin/platelet content of thrombi retrieved with EVT for acute ischemic stroke is strongly associated with increased thrombus stiffness. For thrombi with high platelet values, there was a very strong relationship with thrombus stiffness. Our data provide a basis for future research on the development of next-generation EVT devices tailored to thrombus composition.Medical Instruments & Bio-Inspired Technolog

Quantitative thrombus characteristics on thin-slice computed tomography improve prediction of thrombus histopathology: results of the MR CLEAN Registry

OBJECTIVES: Thrombus computed tomography (CT) characteristics might be used to assess histopathologic thrombus composition in patients treated with endovascular thrombectomy (EVT) for acute ischemic stroke (AIS). We aimed to assess the variability in thrombus composition that could be predicted with combined thrombus CT characteristics. METHODS: Thrombi of patients enrolled in the MR CLEAN Registry between March 2014 and June 2016 were histologically analyzed with hematoxylin-eosin staining and quantified for percentages of red blood cells (RBCs) and fibrin/platelets. We estimated the association between general qualitative characteristics (hyperdense artery sign [HAS], occlusion location, clot burden score [CBS]) and thrombus composition with linear regression, and quantified RBC variability that could be explained with individual and combined characteristics with R2. For patients with available thin-slice (≤ 2.5 mm) imaging, we performed similar analyses for general and quantitative characteristics (HAS, occlusion location, CBS, [relative] thrombus density, thrombus length, perviousness, distance from ICA-terminus). RESULTS: In 332 included patients, the presence of HAS (aβ 7.8 [95% CI 3.9-11.7]) and shift towards a more proximal occlusion location (aβ 3.9 [95% CI 0.6-7.1]) were independently associated with increased RBC and decreased fibrin/platelet content. With general characteristics, 12% of RBC variability could be explained; HAS was the strongest predictor. In 94 patients with available thin-slice imaging, 30% of RBC variability could be explained; thrombus density and thrombus length were the strongest predictors. CONCLUSIONS: Quantitative thrombus CT characteristics on thin-slice admission CT improve prediction of thrombus composition and might be used to further guide clinical decision-making in patients treated with EVT for AIS in the future. KEY POINTS: • With hyperdense artery sign and occlusion location, 12% of variability in thrombus RBC content can be explained. • With hyperdense artery sign, occlusion location, and quantitative thrombus characteristics on thin-slice (≤ 2.5 mm) non-contrast CT and CTA, 30% of variability in thrombus RBC content can be explained. • Absolute thrombus density and thrombus length were the strongest predictors for thrombus composition

Mechanical Characterization of Thrombi Retrieved with Endovascular Thrombectomy in Patients with Acute Ischemic Stroke

Background and Purpose: Mechanical properties of thromboemboli play an important role in the efficacy of endovascular thrombectomy (EVT) for acute ischemic stroke. However, very limited data on mechanical properties of human stroke thrombi are available. We aimed to mechanically characterize thrombi retrieved with EVT, and to assess the relationship between thrombus composition and thrombus stiffness. Methods: Forty-one thrombi from 19 patients with acute stroke who underwent EVT between July and October 2019 were mechanically analyzed, directly after EVT. We performed unconfined compression experiments and determined tangent modulus at 75% strain (Et75) as a measure for thrombus stiffness. Thrombi were histologically analyzed for fibrin/platelets, erythrocytes, leukocytes, and platelets, and we assessed the relationship between histological components and Et75with univariable and multivariable linear mixed regression. Results: Median Et75was 560 (interquartile range, 393-1161) kPa. In the multivariable analysis, fibrin/platelets were associated with increased Et75(aβ, 9 [95% CI, 5 to 13]) kPa, erythrocytes were associated with decreased Et75%(aβ,-9 [95% CI,-5 to-13]) kPa. We found no association between leukocytes and Et75. High platelet values were strongly associated with increased Et75(aβ, 56 [95% CI, 38-73]). Conclusions: Fibrin/platelet content of thrombi retrieved with EVT for acute ischemic stroke is strongly associated with increased thrombus stiffness. For thrombi with high platelet values, there was a very strong relationship with thrombus stiffness. Our data provide a basis for future research on the development of next-generation EVT devices tailored to thrombus composition

Endovascular treatment for calcified cerebral emboli in patients with acute ischemic stroke

OBJECTIVE Calcified cerebral emboli (CCE) are a rare cause of acute ischemic stroke. The authors aimed to assess the association of CCE with functional outcome, successful reperfusion, and mortality. Furthermore, they aimed to assess the effectiveness of intravenous alteplase treatment and endovascular treatment (EVT), as well as the best first-line EVT approach in patients with CCE. METHODS The Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry is a prospective, observational multicenter registry of patients treated with EVT for acute ischemic stroke in 16 intervention hospitals in the Netherlands. The association of CCE with functional outcome, reperfusion, and mortality was evaluated using logistic regression models. Univariable comparisons were made to determine the effectiveness of intravenous alteplase treatment and the best first-line EVT approach in CCE patients. RESULTS The study included 3077 patients from the MR CLEAN Registry. Fifty-five patients (1.8%) had CCE. CCE were not significantly associated with worse functional outcome (adjusted common OR 0.71, 95% CI 0.44-1.15), and 29% of CCE patients achieved functional independence. An extended Thrombolysis in Cerebral Infarction score ≥ 2B was significantly less often achieved in CCE patients compared to non-CCE patients (adjusted OR [aOR] 0.52, 95% CI 0.28- 0.97). Symptomatic intracranial hemorrhage occurred in 8 CCE patients (15%) vs 171 of 3022 non-CCE patients (6%; p = 0.01). The median improvement on the National Institutes of Health Stroke Scale (NIHSS) was 2 in CCE patients versus 4 in non-CCE patients (p = 0.008). CCE were not significantly associated with mortality (aOR 1.16, 95% CI 0.64-2.12). Intravenous alteplase use in CCE patients was not associated with functional outcome or reperfusion. In CCE patients with successful reperfusion, stent retrievers were more often used as the primary treatment device (p = 0.04). CONCLUSIONS While patients with CCE had significantly lower reperfusion rates and less improvement on the NIHSS after EVT, CCE were not significantly associated with worse functional outcome or higher mortality rates. Therefore, EVT should still be considered in this specific group of patients

Endovascular treatment for calcified cerebral emboli in patients with acute ischemic stroke

OBJECTIVE Calcified cerebral emboli (CCE) are a rare cause of acute ischemic stroke. The authors aimed to assess the association of CCE with functional outcome, successful reperfusion, and mortality. Furthermore, they aimed to assess the effectiveness of intravenous alteplase treatment and endovascular treatment (EVT), as well as the best first-line EVT approach in patients with CCE. METHODS The Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry is a prospective, observational multicenter registry of patients treated with EVT for acute ischemic stroke in 16 intervention hospitals in the Netherlands. The association of CCE with functional outcome, reperfusion, and mortality was evaluated using logistic regression models. Univariable comparisons were made to determine the effectiveness of intravenous alteplase treatment and the best first-line EVT approach in CCE patients. RESULTS The study included 3077 patients from the MR CLEAN Registry. Fifty-five patients (1.8%) had CCE. CCE were not significantly associated with worse functional outcome (adjusted common OR 0.71, 95% CI 0.44-1.15), and 29% of CCE patients achieved functional independence. An extended Thrombolysis in Cerebral Infarction score ≥ 2B was significantly less often achieved in CCE patients compared to non-CCE patients (adjusted OR [aOR] 0.52, 95% CI 0.28- 0.97). Symptomatic intracranial hemorrhage occurred in 8 CCE patients (15%) vs 171 of 3022 non-CCE patients (6%; p = 0.01). The median improvement on the National Institutes of Health Stroke Scale (NIHSS) was 2 in CCE patients versus 4 in non-CCE patients (p = 0.008). CCE were not significantly associated with mortality (aOR 1.16, 95% CI 0.64-2.12). Intravenous alteplase use in CCE patients was not associated with functional outcome or reperfusion. In CCE patients with successful reperfusion, stent retrievers were more often used as the primary treatment device (p = 0.04). CONCLUSIONS While patients with CCE had significantly lower reperfusion rates and less improvement on the NIHSS after EVT, CCE were not significantly associated with worse functional outcome or higher mortality rates. Therefore, EVT should still be considered in this specific group of patients

Endovascular treatment for calcified cerebral emboli in patients with acute ischemic stroke

OBJECTIVE Calcified cerebral emboli (CCE) are a rare cause of acute ischemic stroke. The authors aimed to assess the association of CCE with functional outcome, successful reperfusion, and mortality. Furthermore, they aimed to assess the effectiveness of intravenous alteplase treatment and endovascular treatment (EVT), as well as the best first-line EVT approach in patients with CCE. METHODS The Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry is a prospective, observational multicenter registry of patients treated with EVT for acute ischemic stroke in 16 intervention hospitals in the Netherlands. The association of CCE with functional outcome, reperfusion, and mortality was evaluated using logistic regression models. Univariable comparisons were made to determine the effectiveness of intravenous alteplase treatment and the best first-line EVT approach in CCE patients. RESULTS The study included 3077 patients from the MR CLEAN Registry. Fifty-five patients (1.8%) had CCE. CCE were not significantly associated with worse functional outcome (adjusted common OR 0.71, 95% CI 0.44-1.15), and 29% of CCE patients achieved functional independence. An extended Thrombolysis in Cerebral Infarction score ≥ 2B was significantly less often achieved in CCE patients compared to non-CCE patients (adjusted OR [aOR] 0.52, 95% CI 0.28- 0.97). Symptomatic intracranial hemorrhage occurred in 8 CCE patients (15%) vs 171 of 3022 non-CCE patients (6%; p = 0.01). The median improvement on the National Institutes of Health Stroke Scale (NIHSS) was 2 in CCE patients versus 4 in non-CCE patients (p = 0.008). CCE were not significantly associated with mortality (aOR 1.16, 95% CI 0.64-2.12). Intravenous alteplase use in CCE patients was not associated with functional outcome or reperfusion. In CCE patients with successful reperfusion, stent retrievers were more often used as the primary treatment device (p = 0.04). CONCLUSIONS While patients with CCE had significantly lower reperfusion rates and less improvement on the NIHSS after EVT, CCE were not significantly associated with worse functional outcome or higher mortality rates. Therefore, EVT should still be considered in this specific group of patients

Thrombus radiomics in patients with anterior circulation acute ischemic stroke undergoing endovascular treatment

Background: Thrombus radiomics (TR) describe complex shape and textural thrombus imaging features. We aimed to study the relationship of TR extracted from non-contrast CT with procedural and functional outcome in endovascular-treated patients with acute ischemic stroke. Methods: Thrombi were segmented on thin-slice non-contrast CT (≤1 mm) from 699 patients included in the MR CLEAN Registry. In a pilot study, we selected 51 TR with consistent values across two raters' segmentations (ICC >0.75). Random forest models using TR in addition or as a substitute to baseline clinical variables (CV) and manual thrombus measurements (MTM) were trained with 499 patients and evaluated on 200 patients for predicting successful reperfusion (extended Thrombolysis in Cerebral Ischemia (eTICI) ≥2B), first attempt reperfusion, reperfusion within three attempts, and functional independence (modified Rankin Scale (mRS) ≤2). Three texture and shape features were selected based on feature importance and related to eTICI ≥2B, number of attempts to eTICI ≥2B, and 90-day mRS with ordinal logistic regression. Results: Random forest models using TR, CV or MTM had comparable predictive performance. Thrombus texture (inverse difference moment normalized) was independently associated with reperfusion (adjusted common OR (acOR) 0.85, 95% CI 0.72 to 0.99). Thrombus volume and texture were also independently associated with the number of attempts to successful reperfusion (acOR 1.36, 95% CI 1.03 to 1.88 and acOR 1.24, 95% CI 1.04 to 1.49). Conclusions: TR describing thrombus volume and texture were associated with more attempts to successful reperfusion. Compared with models using CV and MTM, TR had no added value for predicting procedural and functional outcome