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Detection of extracellular genomic DNA scaffold in human thrombus: implications for the use of deoxyribonuclease enzymes in thrombolysis

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@article{6dab34ebde474102a8db564732a31b4a,
title = "Detection of extracellular genomic DNA scaffold in human thrombus: implications for the use of deoxyribonuclease enzymes in thrombolysis",
abstract = "PURPOSE: Mechanisms underlying transition of a thrombus susceptible to tissue plasminogen activator (TPA) fibrinolysis to one that is resistant is unclear. Demonstration of a new possible thrombus scaffold may open new avenues of research in thrombolysis and may provide mechanistic insight into thrombus remodeling.MATERIALS AND METHODS: Ten human thrombus samples were collected during cases of thrombectomy and open surgical repair of abdominal aortic aneurysms (five samples < 3 d old and five samples > 1 y old). Additionally, an acute murine hindlimb ischemia model was created to evaluate thrombus samples in mice. Human sections were immunostained for the H2A/H2B/DNA complex, myeloperoxidase, fibrinogen, and von Willebrand factor. Mouse sections were immunostained with the H2A antibody. All samples were further evaluated after hematoxylin and eosin and Masson trichrome staining.RESULTS: An extensive network of extracellular histone/DNA complex was demonstrated in the matrix of human ex vivo thrombus. This network is present throughout the highly cellular acute thrombus. However, in chronic thrombi, detection of the histone/DNA network was predominantly in regions of low collagen content and high cell density, which were mostly near the lumen. These regions of high cell density contained neutrophils and monocytes. Similarly, sections from the acute murine hindlimb ischemia model also exhibited extensive immunoreactivity to the histone antibody in the extracellular space within murine thrombi.CONCLUSIONS: Extensive detection of genomic DNA associated with histones in the extracellular matrix of human and mouse thrombi suggest the presence of a new thrombus-associated scaffold.",
keywords = "Adult, Aged, Aged, 80 and over, Angiography, Digital Subtraction, Animals, Aortic Aneurysm, Abdominal, DNA, Deoxyribonucleases, Disease Models, Animal, Extracellular Matrix Proteins, Female, Fibrinolytic Agents, Hindlimb, Histones, Humans, Immunohistochemistry, Ischemia, Laser-Doppler Flowmetry, Male, Mice, Middle Aged, Monocytes, Muscle, Skeletal, Neutrophils, Thrombolytic Therapy, Thrombosis, Time Factors, Tomography, X-Ray Computed",
author = "Rahmi Oklu and Hassan Albadawi and Watkins, {Michael T} and Marc Monestier and Martin Sillesen and Stephan Wicky",
note = "Copyright {\textcopyright} 2012 SIR. Published by Elsevier Inc. All rights reserved.",
year = "2012",
month = may,
doi = "10.1016/j.jvir.2012.01.072",
language = "English",
volume = "23",
pages = "712--8",
journal = "Journal of Vascular and Interventional Radiology",
issn = "1051-0443",
publisher = "Elsevier Inc",
number = "5",

}

RIS

TY - JOUR

T1 - Detection of extracellular genomic DNA scaffold in human thrombus

T2 - implications for the use of deoxyribonuclease enzymes in thrombolysis

AU - Oklu, Rahmi

AU - Albadawi, Hassan

AU - Watkins, Michael T

AU - Monestier, Marc

AU - Sillesen, Martin

AU - Wicky, Stephan

N1 - Copyright © 2012 SIR. Published by Elsevier Inc. All rights reserved.

PY - 2012/5

Y1 - 2012/5

N2 - PURPOSE: Mechanisms underlying transition of a thrombus susceptible to tissue plasminogen activator (TPA) fibrinolysis to one that is resistant is unclear. Demonstration of a new possible thrombus scaffold may open new avenues of research in thrombolysis and may provide mechanistic insight into thrombus remodeling.MATERIALS AND METHODS: Ten human thrombus samples were collected during cases of thrombectomy and open surgical repair of abdominal aortic aneurysms (five samples < 3 d old and five samples > 1 y old). Additionally, an acute murine hindlimb ischemia model was created to evaluate thrombus samples in mice. Human sections were immunostained for the H2A/H2B/DNA complex, myeloperoxidase, fibrinogen, and von Willebrand factor. Mouse sections were immunostained with the H2A antibody. All samples were further evaluated after hematoxylin and eosin and Masson trichrome staining.RESULTS: An extensive network of extracellular histone/DNA complex was demonstrated in the matrix of human ex vivo thrombus. This network is present throughout the highly cellular acute thrombus. However, in chronic thrombi, detection of the histone/DNA network was predominantly in regions of low collagen content and high cell density, which were mostly near the lumen. These regions of high cell density contained neutrophils and monocytes. Similarly, sections from the acute murine hindlimb ischemia model also exhibited extensive immunoreactivity to the histone antibody in the extracellular space within murine thrombi.CONCLUSIONS: Extensive detection of genomic DNA associated with histones in the extracellular matrix of human and mouse thrombi suggest the presence of a new thrombus-associated scaffold.

AB - PURPOSE: Mechanisms underlying transition of a thrombus susceptible to tissue plasminogen activator (TPA) fibrinolysis to one that is resistant is unclear. Demonstration of a new possible thrombus scaffold may open new avenues of research in thrombolysis and may provide mechanistic insight into thrombus remodeling.MATERIALS AND METHODS: Ten human thrombus samples were collected during cases of thrombectomy and open surgical repair of abdominal aortic aneurysms (five samples < 3 d old and five samples > 1 y old). Additionally, an acute murine hindlimb ischemia model was created to evaluate thrombus samples in mice. Human sections were immunostained for the H2A/H2B/DNA complex, myeloperoxidase, fibrinogen, and von Willebrand factor. Mouse sections were immunostained with the H2A antibody. All samples were further evaluated after hematoxylin and eosin and Masson trichrome staining.RESULTS: An extensive network of extracellular histone/DNA complex was demonstrated in the matrix of human ex vivo thrombus. This network is present throughout the highly cellular acute thrombus. However, in chronic thrombi, detection of the histone/DNA network was predominantly in regions of low collagen content and high cell density, which were mostly near the lumen. These regions of high cell density contained neutrophils and monocytes. Similarly, sections from the acute murine hindlimb ischemia model also exhibited extensive immunoreactivity to the histone antibody in the extracellular space within murine thrombi.CONCLUSIONS: Extensive detection of genomic DNA associated with histones in the extracellular matrix of human and mouse thrombi suggest the presence of a new thrombus-associated scaffold.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Angiography, Digital Subtraction

KW - Animals

KW - Aortic Aneurysm, Abdominal

KW - DNA

KW - Deoxyribonucleases

KW - Disease Models, Animal

KW - Extracellular Matrix Proteins

KW - Female

KW - Fibrinolytic Agents

KW - Hindlimb

KW - Histones

KW - Humans

KW - Immunohistochemistry

KW - Ischemia

KW - Laser-Doppler Flowmetry

KW - Male

KW - Mice

KW - Middle Aged

KW - Monocytes

KW - Muscle, Skeletal

KW - Neutrophils

KW - Thrombolytic Therapy

KW - Thrombosis

KW - Time Factors

KW - Tomography, X-Ray Computed

U2 - 10.1016/j.jvir.2012.01.072

DO - 10.1016/j.jvir.2012.01.072

M3 - Journal article

C2 - 22525027

VL - 23

SP - 712

EP - 718

JO - Journal of Vascular and Interventional Radiology

JF - Journal of Vascular and Interventional Radiology

SN - 1051-0443

IS - 5

ER -

ID: 44345903