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Insights from thrombi retrieved in stroke due to large vessel occlusion.

ABSTRACT: The recent advances of endovascular procedures to treat stroke due to large cerebral vessel occlusion have made it possible to analyze the retrieved thrombus material. Analysis of cerebral thrombi is emerging as a relevant opportunity to complement the diagnostic workup of etiology, to develop new lytic approaches and to optimize the acute treatment of stroke due to large vessel occlusion. Nonetheless, retrieved thrombi are frequently discarded since their informative potential is often neglected and standards are missing. This review provides an overview of the current knowledge and expanding research relating to thrombus composition analysis in large vessel occlusions. We first discuss the heterogeneity of thrombogenic factors that underlie the thrombotic formation in stroke and its implications to identify stroke etiology and thrombus age. Further, we show that understanding structural characteristics of thrombus is pivotal for the development of new-targeted lytic therapies as well as to improve, through thrombus modeling, the development of thrombectomy devices. Finally, we discuss the on-going attempts to identify a signature of thrombus composition indirectly through imaging and peripheral blood biomarkers, which might in future assist treatment decision-making as well as secondary prevention. Thrombus analysis might contribute to the advancement and optimization of personalized stroke treatments.

SUBMITTER: Bacigaluppi M

PROVIDER: S-EPMC6681524 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Insights from thrombi retrieved in stroke due to large vessel occlusion.

Bacigaluppi Marco M Semerano Aurora A Gullotta Giorgia Serena GS Strambo Davide D

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20190618 8

The recent advances of endovascular procedures to treat stroke due to large cerebral vessel occlusion have made it possible to analyze the retrieved thrombus material. Analysis of cerebral thrombi is emerging as a relevant opportunity to complement the diagnostic workup of etiology, to develop new lytic approaches and to optimize the acute treatment of stroke due to large vessel occlusion. Nonetheless, retrieved thrombi are frequently discarded since their informative potential is often neglecte ...[more]

PMID: 31213164

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Project description:BACKGROUND:Acute ischemic stroke (AIS) due to large vessel occlusion (LVO) is a devastating cerebrovascular disorder, which could benefit from collateral circulation. Proteins associated with acute LVO pathogenesis and endothelial function may appear in blood samples of AIS patients due to LVO, thus permitting development of blood-based biomarkers for its diagnosis and prognosis. METHODS:This study is a single-center, retrospective, observational case-control trial. Consecutive patients who presented at the Department of Neurology of Tongji Hospital were recruited from July 2016 to April 2018. In the discovery phase, a proteomic approach with iTRAQ-based LC-MS/MS was used to investigate the altered proteomic pattern in plasma from patients with AIS due to LVO. In the validation study, Western blots was used to identify biomarkers associated with stroke diagnosis as well as their prognostic value associated with different collateral statuses. RESULTS:For this exploratory study, the proteomic analysis of plasma from 40 patients with AIS due to LVO and 20 healthy controls revealed seven differentially expressed proteins with a 1.2/0.83-fold or greater difference between groups. The four elevated proteins, PPBP (1.58?±?0.78 vs 0.98?±?0.37; P?<?0.001), THBS1 (1.13?±?0.88 vs 0.43?±?0.26; P?<?0.001), LYVE1 (1.61?±?0.55 vs 0.97?±?0.50; P?<?0.001), and IGF2 (1.19?±?0.42 vs 0.86?±?0.24; P?<?0.001), were verified by Western blots analysis in an independent cohort including 33 patients and 33 controls. A strong interaction was observed between the four-protein panel and the diagnosis of AIS due to LVO (AUC 0.947; P?<?0.001). Furthermore, IGF2, LYVE1, and THBS1 were closely associated with collateral status (IGF2 0.115, 95% CI 0.016-0.841, P?=?0.033; LYVE1 0.183, 95% CI 0.036-0.918, P?=?0.039; THBS1 4.257, 95% CI 1.273-14.228, P?=?0.019), and proved to be independent predictors of good outcome (IGF2 0.115, 95% CI 0.015-0.866, P?=?0.036; LYVE1 0.028, 95% CI 0.002-0.334, P?=?0.005; THBS1 3.294, 95% CI 1.158-9.372, P =?0.025) at a 3-month follow-up. CONCLUSIONS:The identified 4-biomarker panel could provide diagnostic aid to the existing imaging modalities for AIS due to LVO, and the prognostic value of IGF2, LYVE1, and THBS1 was proved in predicting functional outcomes related to collateral status. Trial registration ClinicalTrials.gov NCT03122002. Retrospectively registered April 20, 2017. URL of trial registry record: https://www.clinicaltrials.gov/ct2/show/NCT03122002?term=NCT+03122002&rank=1.

Project description:Mechanical thrombectomy (MT) is effective in managing patients with acute ischemic stroke (AIS) caused by large-vessel occlusions and allows for valuable histological analysis of thrombi. However, whether bridging therapy (pretreatment with intravenous thrombolysis before MT) provides additional benefits in patients with middle cerebral artery (MCA) occlusion remains unclear. Therefore, this study aimed to compare the effects of direct MT and bridging therapy, and to elucidate the correlation between thrombus composition and stroke subtypes. Seventy-three patients with acute ischemic stroke who received MT, were eligible for intravenous thrombolysis, and had MCA occlusion were included. We matched 21 direct MT patients with 21 bridging therapy patients using propensity score matching and compared their 3rd-month clinical outcomes. All MCA thrombi (n = 45) were histologically analyzed, and the red blood cell (RBC) and fibrin percentages were quantified. We compared the clot composition according to stroke etiology (large-artery atherosclerosis and cardioembolism) and intravenous thrombolysis application. The baseline characteristics showed no difference between groups except for a higher atrial fibrillation rate and NIHSS score on admission in the direct MT group. We performed a supportive analysis using propensity score matching but could not find any differences in the functional outcome, mortality, and intracerebral hemorrhage. In the histological clot analysis, the cardioembolic clots without intravenous thrombolysis pretreatment had higher RBC (P = 0.042) and lower fibrin (P = 0.042) percentages than the large-artery atherosclerosis thrombi. Similar findings were observed in the thrombi treated with recombinant tissue plasminogen activator (P = 0.012). In conclusion, there was no difference in the functional outcomes between the direct MT and bridging therapy groups. However, randomized trials are needed to elucidate the high ratio of cardioembolism subtype in our group of patients. The histological MCA thrombus composition differed between cardioembolism and large-artery atherosclerosis, and this finding provides valuable information on the underlying pathogenesis and thrombus origin.

Project description:Endovascular treatment (EVT) after ischemic stroke due to emergent large vessel occlusion is usually constrained by a specific window of less than 16 to 24 hours from the time the patient was last known well (LKW). Patients with slow progression and tenacious collateral circulation may persist beyond 16 hours. To estimate the prevalence of salvageable tissues 16 hours or more from LKW after ischemic stroke due to emergent large vessel occlusion and investigate the effectiveness of EVT in delayed large vessel occlusion. In this case-control study, from a total of 8032 patients with stroke or transient ischemic attack who were admitted between January 1, 2012, and December 31, 2018, to a single referral university hospital, 150 patients were retrospectively identified who had an acute ischemic stroke with internal carotid artery or middle cerebral artery occlusion, had a baseline National Institutes of Health Stroke Scale score of 6 or more, and arrived 16 hours or more from time LKW. The decision for EVT was made by a treating physician according to the institutional protocol. Baseline ischemic core, collateral circulation status, and computed tomographic or magnetic resonance perfusion parameters were retrospectively quantified. Follow-up images, evaluated a median of 93 hours (interquartile range, 66-120 hours) after arrival, were used to assess the final infarct and hemorrhagic transformation. The main outcome was the modified Rankin Scale score at 90 days. For 150 patients (81 men [54%]; mean [SD] age at onset, 70.1 [13.0] years; median National Institutes of Health Stroke Scale score, 12 [interquartile range, 8-18]), the median ischemic core volume was 11.5 mL (interquartile range, 0-39.1 mL), the median penumbra volume (>6 seconds) was 55.0 mL (interquartile range, 15-128 mL), and the median mismatch ratio was 4.0 (interquartile range, 0.9-18.3). By the imaging inclusion criteria for EVT trials, there were 50 DAWN (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake-up and Late Presenting Strokes Undergoing Neurointervention With Trevo)-eligible patients (33%), 58 DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke)-eligible patients (39%), and 57 ESCAPE (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times)-eligible patients (38%). Endovascular treatment was performed for 24 patients (16%). In propensity score-matched analyses, EVT was associated with better odds of a 90-day modified Rankin Scale score of 0 to 2 (adjusted odds ratio, 11.08 [95% CI, 1.88-108.60]) and a 90-day modified Rankin Scale score shift (common adjusted odds ratio, 5.17 [95% CI, 1.80-15.62]). Type 2 parenchymal hemorrhage was seen in 3 of 24 patients (13%) who received EVT and in 4 of 126 patients (3%) who received medical management (adjusted odds ratio, 4.06 [95% CI, 0.63-26.30]). In a subgroup of 109 patients who were 24 hours from time LKW, EVT was associated with a favorable mRS shift (common adjusted odds ratio, 10.54 [95% CI, 2.18-59.34]). This study suggests that patients with anterior circulation large vessel occlusion presenting very late (>16 hours to 10 days) from the time they were LKW may benefit from EVT.

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Insights from thrombi retrieved in stroke due to large vessel occlusion.

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Insights from thrombi retrieved in stroke due to large vessel occlusion.

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