Studying Stroke Thrombus Composition After Thrombectomy: What Can We Learn?

Stroke ◽  
2021 ◽  
Author(s):  
Senna Staessens ◽  
Olivier François ◽  
Waleed Brinjikji ◽  
Karen M. Doyle ◽  
Peter Vanacker ◽  
...  
Keyword(s):  
Endovascular Procedures ◽  
Stroke Care ◽  
Lessons Learned ◽  
Success Rates ◽  
Complex Composition ◽  
Comprehensive Overview ◽  
Endovascular Thrombectomy ◽  
Extracellular Traps ◽  
Von Willebrand ◽  
Willebrand Factor

The composition of ischemic stroke thrombi has gained an increasing amount of interest in recent years. The implementation of endovascular procedures in standard stroke care has granted researchers the unique opportunity to examine patient thrombus material. Increasing evidence indicates that stroke thrombi are complex and heterogenous, consisting of various biochemical (eg, fibrin, von Willebrand factor, and neutrophil extracellular traps) and cellular (eg, red blood cells, platelets, leukocytes, and bacteria) components. This complex composition may explain therapeutic limitations and also offer novel insights in several aspects of stroke management. Better understanding of thrombus characteristics could, therefore, potentially lead to improvements in the management of patients with stroke. In this review, we provide a comprehensive overview of the lessons learned by examining stroke thrombus composition after endovascular thrombectomy and its potential relevance for thrombectomy success rates, thrombolysis, clinical outcomes, stroke etiology, and radiological imaging.

scholarly journals Detailed histological analysis of a thrombectomy-resistant ischemic stroke thrombus: a case report

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Senna Staessens ◽  
Olivier François ◽  
Linda Desender ◽  
Peter Vanacker ◽  
Tom Dewaele ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Von Willebrand Factor ◽  
Histological Analysis ◽  
Mechanical Thrombectomy ◽  
Neutrophil Extracellular Traps ◽  
Extracellular Dna ◽  
Extracellular Traps ◽  
First Pass ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Background Mechanical removal of a thrombus by thrombectomy can be quite challenging. For reasons that are not fully understood, some thrombi require multiple passes to achieve successful recanalization, whereas other thrombi are efficiently removed in a single pass. Since first pass success is associated with better clinical outcome, it is important to better understand the nature of thrombectomy resistant thrombi. The aim of this study was therefore to characterize the cellular and molecular composition of a thrombus that was very hard to retrieve via mechanical thrombectomy. Case presentation In a patient that was admitted with a right middle cerebral artery M1-occlusion, 11 attempts using various thrombectomy devices and techniques were required for removal of the thrombus. This peculiar case provided a rare opportunity to perform an in-depth histopathological study of a difficult to retrieve thrombus. Thrombus material was histologically analyzed using hematoxylin and eosin, Martius Scarlet Blue stain (red blood cells and fibrin), Feulgen stain (DNA), von Kossa stain (calcifications) and immunohistochemical analysis of von Willebrand factor, platelets, leukocytes and neutrophil extracellular traps. Histological analysis revealed abnormally high amounts of extracellular DNA, leukocytes, von Willebrand factor and calcifications. Extracellular DNA stained positive for markers of leukocytes and NETs, suggesting that a significant portion of DNA is derived from neutrophil extracellular traps. Conclusion In this unique case of a nearly thrombectomy-resistant stroke thrombus, our study showed an atypical composition compared to the common structural features found in ischemic stroke thrombi. The core of the retrieved thrombus consisted of extracellular DNA that colocalized with von Willebrand factor and microcalcifications. These results support the hypothesis that von Willebrand factor, neutrophil extracellular traps and microcalcifications contribute to mechanical thrombectomy resistance. Such information is important to identify novel targets in order to optimize technical treatment protocols and techniques to increase first pass success rates.

scholarly journals Neutrophil extracellular traps and von Willebrand factor are allies that negatively influence COVID‐19 outcomes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
María P. Fernández‐Pérez ◽  
Sonia Águila ◽  
Laura Reguilón‐Gallego ◽  
Ascensión M. los Reyes‐García ◽  
Antonia Miñano ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Neutrophil Extracellular Traps ◽  
Extracellular Traps ◽  
Von Willebrand ◽  
Willebrand Factor

Impaired adhesion of neutrophils expressing Slc44a2/HNA-3b to VWF protects against NETosis under venous shear rate

Blood ◽  
2021 ◽  
Author(s):  
Gaia Zirka ◽  
Philippe Robert ◽  
Julia Tilburg ◽  
Victoria Tishkova ◽  
Chrissta X Maracle ◽  
...  
Keyword(s):  
Transmembrane Protein ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Wild Type ◽  
Shear Rates ◽  
Extracellular Traps ◽  
Genome Wide ◽  
Healthy Donors ◽  
Von Willebrand ◽  
Willebrand Factor

Genome wide association studies linked expression of the human neutrophil antigen 3b (HNA-3b) epitope on the Slc44a2 protein with a 30% decreased risk of venous thrombosis (VT) in humans. Slc44a2 is a ubiquitous transmembrane protein identified as a receptor for Von Willebrand factor (VWF). To explain the link between Slc44a2 and VT we wanted to determine how Slc44a2 expressing either HNA-3a or HNA-3b on neutrophils could modulate their adhesion and activation on VWF under flow. Transfected HEK293T cells or neutrophils homozygous for the HNA-3a- or the HNA-3b-coding allele were purified from healthy donors and perfused in flow chambers coated with VWF at venous shear rates (100s-1). HNA-3a expression was required for Slc44a2-mediated neutrophil adhesion to VWF at 100s-1. This adhesion could occur independently of β2 integrin and was enhanced when neutrophils are preactivated with lipopolysaccharide (LPS). Moreover, specific shear conditions with high neutrophil concentration could act as a "second hit", inducing the formation of neutrophil extracellular traps. Neutrophil mobilization was also measured by intravital microscopy in venules from SLC44A2-knockout and wild-type mice after histamine-induced endothelial degranulation. Mice lacking Slc44a2 showed a massive reduction in neutrophil recruitment in inflamed mesenteric venules. Our results show that Slc44a2/HNA-3a is important for the adhesion and activation of neutrophils in veins under inflammation and when submitted to specific shears. Neutrophils expressing Slc44a2/HNA-3b not being associated with these observations, these results could thus explain the association between HNA-3b and a reduced risk for VT in humans.

scholarly journals von Willebrand Factor Directly Interacts With DNA From Neutrophil Extracellular Traps

2014 ◽  
Vol 34 (7) ◽  
pp. 1382-1389 ◽  
Author(s):  
S. Grassle ◽  
V. Huck ◽  
K. I. Pappelbaum ◽  
C. Gorzelanny ◽  
C. Aponte-Santamaria ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Neutrophil Extracellular Traps ◽  
Extracellular Traps ◽  
Von Willebrand ◽  
Willebrand Factor

scholarly journals Thrombus Composition and Efficacy of Thrombolysis and Thrombectomy in Acute Ischemic Stroke

Stroke ◽  
2021 ◽  
Author(s):  
Precious Jolugbo ◽  
Robert A.S. Ariëns
Keyword(s):  
Ischemic Stroke ◽  
Blood Cell ◽  
Acute Ischemic Stroke ◽  
Red Blood Cell ◽  
Reference Lists ◽  
Mechanical Thrombectomy ◽  
Extracellular Traps ◽  
Von Willebrand ◽  
The Impact ◽  
Willebrand Factor

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.

Neutrophil Extracellular Traps and von Willebrand Factor in Thrombosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. SCI-30-SCI-30
Author(s):  
Denisa D. Wagner
Keyword(s):  
Von Willebrand Factor ◽  
Ischemia Reperfusion Injury ◽  
Conflicts Of Interest ◽  
Ischemia Reperfusion ◽  
Tumor Biology ◽  
Vena Cava ◽  
Neutrophil Extracellular Traps ◽  
Extracellular Traps ◽  
Von Willebrand ◽  
Willebrand Factor

For many years, my lab has been studying the interplay between inflammation and thrombosis. These processes occur together, stimulate each other and share cellular and molecular components. The latest example of a common functional component is neutrophil extracellular traps (NETs). NETs are chromatin released together with toxic granular components from highly stimulated neutrophils. Originally found to trap/sequester invading pathogens, they were soon also seen to be part of sterile inflammatory and thrombotic processes. They interact with von Willebrand factor (VWF), which is also involved in platelet and leukocyte recruitment and is crucial for venous thrombus development after inferior vena cava stenosis. It is possible that NETs and VWF work together and cleavage of either by DNase 1 or ADAMTS13 is beneficial in ischemia/reperfusion injury. This will be discussed together with the role of NETs and the enzyme that generates them (PAD4) in animal models of deep vein thrombosis, myocardial infarction and in physiological wound healing. Interestingly, we observed that various cancers in mice prime neutrophils for NETosis. This causes cancer-associated thrombosis, and the production of NETs may affect tumor biology. Disclosures No relevant conflicts of interest to declare.

The Role of Immunomodulation in the Management of Factor VIII Inhibitors

Hematology ◽  
2006 ◽  
Vol 2006 (1) ◽  
pp. 421-425 ◽  
Author(s):  
David Lillicrap
Keyword(s):  
Prospective Trial ◽  
Tolerance Induction ◽  
Immunological Tolerance ◽  
Success Rates ◽  
Immune Tolerance Induction ◽  
Fviii Inhibitor ◽  
Risk Patients ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Approximately 25% of persons with hemophilia A will have their treatment complicated by the development of anti-FVIII inhibitory antibodies. This adverse event requires the use of alternative hemostatic agents to treat bleeding and the consideration of a protocol to generate immunological tolerance to FVIII. The pathogenetic factors contributing to FVIII inhibitor generation include both patient- and concentrate-related characteristics. The FVIII genotype contributes to this risk as do other, less well defined, immunogenetic factors. The role of the type of FVIII concentrate as a precipitant for inhibitor generation appears to be less influential. Immunomodulatory management of FVIII inhibitors requires sustained and repeated exposure to FVIII through a variety of intravenous immune tolerance induction (ITI) protocols. Certain pre-ITI characteristics predict for the likelihood of success, most especially the pre-ITI anti-FVIII inhibitor titer. Currently, two major areas of debate remain unresolved with relation to the optimal form of ITI schedule. The best FVIII dose to generate FVIII tolerance is under investigation in an international prospective trial, while the issue of whether von Willebrand factor–containing concentrates may provide more powerful tolerizing effects remains open for further discussion. With a variety of ITI protocols, success rates of approximately 80% have been achieved with good-risk patients. In those that fail initial attempts at ITI, additional treatments using agents such rituximab are now being explored with further evidence of success in 60–80% of these salvage patients. Finally, several pre-clinical studies of innovative approaches to achieving FVIII tolerance suggest that combinations of immunomodulatory therapy may be of benefit in the future.

scholarly journals Activated αIIbβ3 on platelets mediates flow-dependent NETosis via SLC44A2

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Adela Constantinescu-Bercu ◽  
Luigi Grassi ◽  
Mattia Frontini ◽  
Isabelle I Salles-Crawley ◽  
Kevin Woollard ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Extracellular Loop ◽  
Cell Binding ◽  
Vein Thrombosis ◽  
Extracellular Traps ◽  
Von Willebrand ◽  
Deep Vein ◽  
Willebrand Factor ◽  
Insight Into ◽  
Impaired Binding

Platelet-neutrophil interactions are important for innate immunity, but also contribute to the pathogenesis of deep vein thrombosis, myocardial infarction and stroke. Here we report that, under flow, von Willebrand factor/glycoprotein Ibα-dependent platelet ‘priming’ induces integrin αIIbβ3 activation that, in turn, mediates neutrophil and T-cell binding. Binding of platelet αIIbβ3 to SLC44A2 on neutrophils leads to mechanosensitive-dependent production of highly prothrombotic neutrophil extracellular traps. A polymorphism in SLC44A2 (rs2288904-A) present in 22% of the population causes an R154Q substitution in an extracellular loop of SLC44A2 that is protective against venous thrombosis results in severely impaired binding to both activated αIIbβ3 and VWF-primed platelets. This was confirmed using neutrophils homozygous for the SLC44A2 R154Q polymorphism. Taken together, these data reveal a previously unreported mode of platelet-neutrophil crosstalk, mechanosensitive NET production, and provide mechanistic insight into the protective effect of the SLC44A2 rs2288904-A polymorphism in venous thrombosis.

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