Complementary roles of platelets and coagulation in thrombus formation on plaques acutely ruptured by targeted ultrasound treatment: a novel intravital model

Background: Atherothrombosis is a major cause of cardiovascular events. However, animal models to study this process are scarce. Objectives: We describe the first murine model of acute thrombus formation upon plaque rupture to study atherothrombosis by intravital fluorescence microscopy. Methods: Lo...

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Bibliographic Details
Published in:Journal of thrombosis and haemostasis 2009-01, Vol.7 (1), p.152-161
Main Authors: KUIJPERS, M. J. E., GILIO, K., REITSMA, S., NERGIZ‐UNAL, R., PRINZEN, L., HEENEMAN, S., LUTGENS, E., VAN ZANDVOORT, M. A. M. J., NIESWANDT, B., OUDE EGBRINK, M. G. A., HEEMSKERK, J. W. M.
Format: Article
Language:English
Subjects:
animal model
Animals
atherosclerosis
Atherosclerosis - complications
Atherosclerosis - pathology
Blood Coagulation - physiology
Blood Platelets - physiology
Carotid Artery Thrombosis
coagulation
Collagen
Disease Models, Animal
Erythrocytes - pathology
Fibrin
Mice
Microscopy, Fluorescence
plaque rupture
platelet activation
Thrombosis - etiology
Thrombosis - pathology
thrombus formation
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Summary:Background: Atherothrombosis is a major cause of cardiovascular events. However, animal models to study this process are scarce. Objectives: We describe the first murine model of acute thrombus formation upon plaque rupture to study atherothrombosis by intravital fluorescence microscopy. Methods: Localized rupture of an atherosclerotic plaque in a carotid artery from Apoe−/− mice was induced in vivo using ultrasound. Rupture of the plaque and formation of localized thrombi were verified by two‐photon laser scanning microscopy (TPLSM) in isolated arteries, and by immunohistochemistry. The thrombotic reaction was quantified by intravital fluorescence microscopy. Results: Inspection of the ultrasound‐treated plaques by histochemistry and TPLSM demonstrated local damage, collagen exposure, luminal thrombus formation as well as intra‐plaque intrusion of erythrocytes and fibrin. Ultrasound treatment of healthy carotid arteries resulted in endothelial damage and limited platelet adhesion. Real‐time intravital fluorescence microscopy demonstrated rapid platelet deposition on plaques and formation of a single thrombus that remained subocclusive. The thrombotic process was antagonized by thrombin inhibition, or by blocking of collagen or adenosine diphosphate receptor pathways. Multiple thrombi were formed in 70% of mice lacking CD40L. Conclusions: Targeted rupture of murine plaques results in collagen exposure and non‐occlusive thrombus formation. The thrombotic process relies on platelet activation as well as on thrombin generation and coagulation, and is sensitive to established and novel antithrombotic medication. This model provides new possibilities to study atherothrombosis in vivo.
ISSN:1538-7933
1538-7836
1538-7836
DOI:10.1111/j.1538-7836.2008.03186.x