Objective: Neutrophil extracellular traps (NETs) have been shown to promote thrombus formation. Little is known about the exact composition of thrombi that cause ischemic stroke. In particular no information is yet available on the presence of NETs in cerebral occlusions. Such information is however essential to improve current thrombolytic therapy with t-PA. This study aimed at investigating the presence of neutrophils and more specifically NETs in ischemic stroke thrombi.

Methods: Sixty-eight thrombi retrieved from ischemic stroke patients undergoing endovascular treatment were characterized by immunostaining using neutrophil markers (CD66b and neutrophil elastase) and NETs markers (citrullinated histones H3 (H3Cit) and extracellular DNA). Neutrophils and NETs were quantified. In addition, extracellular DNA was targeted by performing ex vivo lysis of retrieved thrombi with DNase 1 and t-PA.

Results: Neutrophils were detected extensively throughout all thrombi. Citrullinated histones H3 (H3Cit), a hallmark of NETs, were observed in almost all thrombi. H3Cit-positive area varied up to 13.45% of total thrombus area. Co-localization of H3Cit with extracellular DNA released from neutrophils confirmed the specific presence of NETs. H3Cit was more abundant in thrombi from cardioembolic origin compared to other etiologies. Older thrombi contained significantly more neutrophils and H3Cit compared to fresh thrombi. Interestingly, ex vivo lysis of patient thrombi was more successful when adding DNase 1 to standard t-PA.

Interpretation: Neutrophils and NETs form important constituents of cerebral thrombi. Targeting of NETs with DNase 1 might have prothrombolytic potential in treatment of acute ischemic stroke. This article is protected by copyright. All rights reserved.

Neutrophil extracellular traps in ischemic stroke thrombi.

Thrombi retrieved from patients with acute ischemic stroke are highly heterogeneous. Recent data suggest that thrombus composition may impact on mechanical thrombectomy, the number of recanalization manoeuvres, resistance to retrieval, and on thrombolytic potential. Our aim was to summarize evidence describing the impact of thrombus composition on efficacy of mechanical thrombectomy and thrombolysis in patients with acute ischemic stroke. The scoping review methodology guided by the Joanna Briggs Institute, an adaption of the Arksey and O'Malley, was followed. Comprehensive searches were conducted in MEDLINE, EMBASE, SCOPUS, and Web of Science. Articles were classified into 4 key themes: (1) composition of stroke thrombi, (2) thrombus composition and mechanical thrombectomy, (3) thrombus composition and thrombolytic therapy, and (4) novel imaging and endovascular approaches. Our search identified 698 articles published from 1987 to June 2020. Additional articles were extracted from reference lists of the selected articles. Overall, 95 topic-specific articles identified for inclusion published in 40 different journals were included. Reports showed that thrombus composition in stroke was highly heterogeneous, containing fibrin, platelets, red blood cells, VWF (von Willebrand Factor), and neutrophil extracellular traps. Thrombi could roughly be divided into fibrin- and red blood cell-rich clots. Fibrin-rich clots were associated with increased recanalization manoeuvres, longer procedure time, and less favorable clinical outcomes compared with red blood cell-rich clots. Advances in detection or treatment of thrombi that take into account clot heterogeneity may be able to improve future endovascular and thrombolytic treatment of stroke.

/pdf/thrombus-composition-and-efficacy-of-thrombolysis-and-36uqgcng44.pdf

Thrombus Composition and Efficacy of Thrombolysis and Thrombectomy in Acute Ischemic Stroke.

Background and Purpose— Ischemic stroke of undetermined cause is a major health issue because of its high frequency and clinical relevance. Histopathologic analysis of human thrombi, retrieved from stroke patients with large-vessel occlusion during mechanical thrombectomy, may provide information about underlying pathologies. This study examines the relationship between stroke causes and histological clot composition to identify specific patterns that might help to distinguish causes of cryptogenic stroke.

Methods— Thrombi of 145 consecutive stroke patients with large-vessel occlusion were collected during intracranial mechanical recanalization. The hematoxylin and eosin–stained specimens were quantitatively analyzed in terms of the relative fractions of the main constituents (red and white blood cells and fibrin/platelets). These data, along with additional clinical and interventional parameters, were compared for different stroke subtypes, as defined by the international Trial of Org 10172 in Acute Stroke Treatment criteria.

Results— The composition of thrombi from cardioembolic and noncardioembolic stroke patients differed significantly for all main thrombus components. Cardioembolic thrombi had higher proportions of fibrin/platelets ( P =0.009), less erythrocytes ( P =0.003), and more leucocytes ( P =0.035) than noncardioembolic thrombi. Cryptogenic strokes showed strong overlap with cardioembolic strokes but not with noncardioembolic strokes, in terms of both thrombus histology and interventional and clinical outcome parameters.

Conclusions— Quantitative evaluation of thrombus composition may help to distinguish between different stroke causes. Our findings support the notion that the majority of cryptogenic strokes are cardioembolic.

ftp://ftp.ncbi.nlm.nih.gov/pub/pmc/b2/ae/Br_J_Cancer_1998_77(1)_123-124.tar.gz

Thrombus Histology Suggests Cardioembolic Cause in Cryptogenic Stroke

Background and purpose Studying the imaging and histopathologic characteristics of thrombi in ischemic stroke could provide insights into stroke etiology and ideal treatment strategies We conducted a systematic review of imaging and histologic characteristics of thrombi in acute ischemic stroke Materials and methods We identified all studies published between January 2005 and December 2015 that reported findings related to histologic and/or imaging characteristics of thrombi in acute ischemic stroke secondary to large vessel occlusion The five outcomes examined in this study were (1) association between histologic composition of thrombi and stroke etiology; (2) association between histologic composition of thrombi and angiographic outcomes; (3) association between thrombi imaging and histologic characteristics; (4) association between thrombi imaging characteristics and angiographic outcomes; and (5) association between imaging characteristics of thrombi and stroke etiology A meta-Analysis was performed using a random effects model Results There was no significant difference in the proportion of red blood cell (RBC)-rich thrombi between cardioembolic and large artery atherosclerosis etiologies (OR 162, 95% CI 01 to 280, p=063) Patients with a hyperdense artery sign had a higher odds of having RBC-rich thrombi than those without a hyperdense artery sign (OR 90, 95% CI 26 to 312, p<001) Patients with a good angiographic outcome had a mean thrombus Hounsfield unit (HU) of 551±31 compared with a mean HU of 484±19 for patients with a poor angiographic outcome (mean standard difference 65, 95% CI 27 to 102, p<0001) There was no association between imaging characteristics and stroke etiology (OR 113, 95% CI 032 to 400, p=085) Conclusions The hyperdense artery sign is associated with RBC-rich thrombi and improved recanalization rates However, there was no association between the histopathological characteristics of thrombi and stroke etiology and angiographic outcomes

https://jnis.bmj.com/content/neurintsurg/9/6/529.full.pdf

Correlation of imaging and histopathology of thrombi in acute ischemic stroke with etiology and outcome: a systematic review

Background and Purpose— The introduction of stent retrievers allows for a complete extraction and histological analysis of human thrombi. Ischemic stroke is a major health issue, and differentiation of underlying causes is highly relevant to prevent recurrent stroke. Therefore, histopathologic analysis of the embolic clots after removal may provide valuable information about underlying pathologies. This study analyzes histological clot composition and aims to identify specific patterns that might help to distinguish causes of ischemic stroke. Methods— Patients with occlusion of the carotid-T or middle cerebral artery who underwent thrombectomy at our university medical center between December 2013 and February 2016 were included. Samples were histologically analyzed (hematoxylin and eosin, Elastica van Gieson, and Prussian blue), additionally immunohistochemistry for CD3, CD20, and CD68/KiM1P was performed. These data, along with additional clinical and interventional parameters, were compared for different stroke subtypes, as defined by the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification. Results— One hundred eighty-seven patients were included, of these, in 77 patients, cardioembolic; in 46 patients, noncardioembolic; and in 64 patients, cryptogenic pathogenesis was determined. Cardioembolic thrombi had higher proportions of fibrin/platelets ( P =0.027), less erythrocytes ( P =0.005), and more leucocytes ( P =0.026) than noncardioembolic thrombi. We observed a strong overlap of cryptogenic strokes and cardioembolic strokes concerning thrombus histology. The immunohistochemical parameters CD3, CD20, and CD68/KiM1P showed no statistically noticeable differences between stroke subtypes. Conclusions— Histological thrombus features vary significantly according to the underlying cause and may help to differentiate between cardioembolic and noncardioembolic stroke. In addition, our study supports the hypothesis that most cryptogenic strokes have a cardioembolic cause.

Ischemic Stroke: What Does the Histological Composition Tell Us About the Origin of the Thrombus?

BACKGROUND AND PURPOSE: It is unclear whether clot composition analysis is helpful to predict a stroke mechanism in acute large vessel occlusion. In addition, the relationship between early vessel signs on imaging studies and clot compositions has been poorly understood. The purpose of this study was to elucidate the relationship between clot composition and stroke etiology following mechanical thrombectomy and to investigate the effect of varied clot compositions on gradient-echo MR imaging of clots. MATERIALS AND METHODS: Histopathologic analysis of retrieved clots from 37 patients with acute MCA occlusion was performed. Patients underwent gradient-echo imaging before endovascular therapy. Retrieved clots underwent semiquantitative proportion analysis to quantify red blood cells, fibrin, platelets, and white blood cells by area. Correlations between clot compositions and stroke subtypes and susceptibility vessel signs on gradient-echo imaging were assessed. RESULTS: Stroke etiology was classified as cardioembolism in 22 patients (59.4%), large-artery atherosclerosis in 8 (21.6%), and undetermined in 7 (18.9%). The clots from cardioembolism had a significantly higher proportion of red blood cells (37.8% versus 16.9%, P = .031) and a lower proportion of fibrin (32.3% versus 48.5%, P = .044) compared with those from large-artery atherosclerosis. The proportion of red blood cells was significantly higher in clots with a susceptibility vessel sign than in those without it (48.0% versus 1.9%, P CONCLUSIONS: The histologic composition of clots retrieved from cerebral arteries in patients with acute stroke differs between those with cardioembolism and large-artery atherosclerosis. In addition, a susceptibility vessel sign on gradient-echo imaging is strongly associated with a high proportion of red blood cells and a low proportion of fibrin and platelets in retrieved clots.

http://www.ajnr.org/content/ajnr/36/9/1756.full.pdf

Histologic Analysis of Retrieved Clots in Acute Ischemic Stroke: Correlation with Stroke Etiology and Gradient-Echo MRI

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Histologic Analysis of Retrieved Clots in Acute Ischemic Stroke: Correlation with Stroke Etiology and Gradient-Echo MRI