Platelet-rich emboli are associated with von Willebrand factor levels and have poorer revascularization outcomes

Douglas, Andrew; Fitzgerald, Seán; Mereuta, Oana Madalina; Rossi, Rosanna; O’Leary, Seán; Pandit, Abhay; McCarthy, Ray; Gilvarry, Michael; Holmegaard, Lukas; Abrahamsson, Margareta; Jerndal, Mikael; Dehlfors, Niclas; Brennan, Paul; Power, Sarah; O’Hare, Alan; Griffin, Emma; Kallmes, David F.; Brinjikji, Waleed; Szikora, István; Tatlısumak, Turgut; Rentzos, Alexandros; Thornton, John; Doyle, Karen M.

doi:10.1136/neurintsurg-2019-015410

Cited by 44 publications

(71 citation statements)

References 33 publications

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“…We did not observe significant CD42b-vWF presence in any of the serial sections from age- and sex-matched C57BL/6 mice although there were some sections that exhibited detectable CD42b-vWF (not shown). The presence of CD42b and vWF in a manner that appears to be extra/peri-vascular suggested that a substantial anomaly is occuring in the vascularization ( 61 – 66 ) of the non-endocrine tissue of NOD pancreata, at least in mice at 2 weeks of age. We proposed that any vascular anomaly would be reflected in an upregulation of P-selectin on the endothelium of these blood vessels.…”

Section: Resultsmentioning

confidence: 99%

Neutrophil-Associated Inflammatory Changes in the Pre-Diabetic Pancreas of Early-Age NOD Mice

et al. 2021

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A growing body of evidence indicates that neutrophils are the first major leukocyte population accumulating inside the pancreas even before the onset of a lymphocytic-driven impairment of functional beta cells in type 1 diabetes mellitus (T1D). In humans, pancreata from T1D deceased donors exhibit significant neutrophil accumulation. We present a time course of previously unknown inflammatory changes that accompany neutrophil and neutrophil elastase accumulation in the pancreas of the non-obese diabetic (NOD) mouse strain as early as 2 weeks of age. We confirm earlier findings in NOD mice that neutrophils accumulate as early as 2 weeks of age. We also observe a concurrent increase in the expression of neutrophil elastase in this time period. We also detect components of neutrophil extracellular traps (NET) mainly in the exocrine tissue of the pancreas during this time as well as markers of vascular pathology as early as 2 weeks of age. Age- and sex-matched C57BL/6 mice do not exhibit these features inside the pancreas. When we treated NOD mice with inhibitors of myeloperoxidase and neutrophil elastase, two key effectors of activated neutrophil activity, alone or in combination, we were unable to prevent the progression to hyperglycemia in any manner different from untreated control mice. Our data confirm and add to the body of evidence demonstrating neutrophil accumulation inside the pancreas of mice genetically susceptible to T1D and also offer novel insights into additional pathologic mechanisms involving the pancreatic vasculature that have, until now, not been discovered inside the pancreata of these mice. However, inhibition of key neutrophil enzymes expressed in activated neutrophils could not prevent diabetes. These findings add to the body of data supporting a role for neutrophils in the establishment of early pathology inside the pancreas, independently of, and earlier from the time at onset of lymphocytic infiltration. However, they also suggest that inhibition of neutrophils alone, acting via myeloperoxidase and neutrophil elastase only, in the absence of other other effector cells, is insufficient to alter the natural course of autoimmune diabetes, at least in the NOD model of the disease.

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Section: Resultsmentioning

confidence: 99%

Neutrophil-Associated Inflammatory Changes in the Pre-Diabetic Pancreas of Early-Age NOD Mice

et al. 2021

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“…Increased levels of platelets and calcium may also render 'white' clots stiffer and impact the MT outcome. [14,17] However, despite the platelet-rich composition of 'white' clots compared to 'red' clots in our cohort, there was no signi cant difference in terms of number of passes during MT and nal modi ed Thrombolysis in Cerebral Infarction (mTICI) score.…”

Section: Discussionmentioning

confidence: 63%

“…We acknowledge that there are also other components in the platelets/other-rich areas identi ed by MSB so we performed immunohistochemistry to distinguish between platelets and platelet-related factors such as vWF. [14] The high expression of CD42b and vWF in our 'white' clots highlights their critical role in 'white' clots formation. Recent studies have described important histological features that may explain the recombinant tissue plasminogen activator (rtPA)-resistance of AIS thrombi: the presence of a dense outer shell containing mainly platelets, vWF and extracellular DNA as well as the presence in the plateletrich thrombi of dense brin structures lined with vWF, extracellular DNA and lled with platelets.…”

Section: Discussionmentioning

confidence: 97%

Characterization of the ‘White’ Appearing Clots that Cause Acute Ischemic Stroke

Mereuta

Fitzgerald

Rossi

et al. 2020

Preprint

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Background: Most clots retrieved from patients with acute ischemic stroke are ‘red’ in color and are predominantly composed of red blood cells and fibrin. ‘White’ clots represent a less common entity and their histological composition is largely unknown.The aim of this study was to investigate the composition, imaging and procedural characteristics of ‘white’ clots retrieved by mechanical thrombectomy.Materials and Methods:Nineteen ‘white’ thrombi selected by visual inspection from 293 cases were collected as part of the multi-institutional RESTORE registry. Non-contrast computed tomography (NCCT), histological and immunohistochemical analyses were performed. Components were quantified using Orbit Image Analysis.Results:Quantification of Martius Scarlett Blue stain identified platelets/other as the major component in ‘white’ clots’ (63%) followed by fibrin (26%), red blood cells (7%) and white blood cells (4%). ‘White’ clots presented significantly more platelets/other and less red blood cells compared to the ‘red’ clots which showed a mean of 23% and 44%, respectively. The mean platelet (CD42b) content in ‘white’ clots was 43%; von Willebrand Factor (vWF) mean expression was 38%.Collagen and calcification were associated in one case. Fatty acid binding protein 4 was expressed in two cases.‘White’ clots were also significantly smaller (9.5 versus 12 mm) and less hyperdense (52 versus 61 Hounsfield Units) on NCCT compared to the other cases.Conclusions:‘White’ clots represented 6% of our cohort and are platelet and vWF-rich. Calcification, collagen and adipocytes were found occasionally. ‘White’ clots differ from other clots in composition, size and density on NCCT.

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“…Platelet and von Willebrand factor (vWF) levels are useful additional hallmarks of clot composition. [24][25][26] Immunohistochemical staining for platelets (CD42b) and the vWF was performed on a Bond RX autostainer (Leica Biosystems). Antigen retrieval with Tris-EDTA was performed for platelet staining (anti-CD42b); no antigen retrieval was used for vWF staining.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Histologic quantification was performed on the digital slide using Image Analysis Software (Orbit; www.Orbit.bio) as described previously. 21,25 The percentage area of each component (RBC, WBC, fibrin, and platelet/other) within the clot was calculated for the histologic staining with MSB. 21 The percentage area of positive immunohistochemistry staining was calculated separately for CD42b and vWF.…”

Section: Imaging and Quantificationmentioning

confidence: 99%

Novel Human Acute Ischemic Stroke Blood Clot Analogs for In Vitro Thrombectomy Testing

Fitzgerald¹,

Liu²,

Dai³

et al. 2021

AJNR Am J Neuroradiol

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BACKGROUND AND PURPOSE: Previous studies have successfully created blood clot analogs for in vitro endovascular device testing using animal blood of various species. Blood components vary greatly among species; therefore, creating clot analogs from human blood is likely a more accurate representation of thrombi formed in the human vasculature. MATERIALS AND METHODS:Following approval from the Mayo Clinic institutional review board, human whole-blood and platelet donations were obtained from the blood transfusion service. Twelve clot analogs were created by combining different ratios of red blood cells 1 buffy coat, plasma, and platelets. Thrombin and calcium chloride were added to stimulate coagulation. Clot composition was assessed using histologic and immunohistochemical staining. To assess the similarities of mechanical properties to patient clots, 3 types of clot analogs (soft, elastic, and stiff) were selected for in vitro thrombectomy testing.

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Platelet-rich emboli are associated with von Willebrand factor levels and have poorer revascularization outcomes

Cited by 44 publications

References 33 publications

Neutrophil-Associated Inflammatory Changes in the Pre-Diabetic Pancreas of Early-Age NOD Mice

Neutrophil-Associated Inflammatory Changes in the Pre-Diabetic Pancreas of Early-Age NOD Mice

Characterization of the ‘White’ Appearing Clots that Cause Acute Ischemic Stroke

Novel Human Acute Ischemic Stroke Blood Clot Analogs for In Vitro Thrombectomy Testing

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