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Coagulation & its Disorders
Ferrata Storti Foundation
Haematologica 2020 Volume 105(2):498-507
Structural analysis of ischemic stroke thrombi: histological indications for therapy resistance
Senna Staessens,1 Frederik Denorme,1 Olivier François,2 Linda Desender,1 Tom Dewaele,2 Peter Vanacker,3,4,5 Hans Deckmyn,1 Karen Vanhoorelbeke,1 Tommy Andersson2,6 and Simon F. De Meyer1
1Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium; 2Department of Medical Imaging, AZ Groeninge, Kortrijk, Belgium; 3Department of Neurology, AZ Groeninge, Kortrijk, Belgium; 4Department of Neurology, University Hospitals Antwerp, Antwerp, Belgium; 5Department of Translational Neuroscience, University of Antwerp, Antwerp, Belgium and 6Department of Neuroradiology, Karolinska University Hospital and Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
ABSTRACT
Ischemic stroke is caused by a thromboembolic occlusion of cerebral arteries. Treatment is focused on fast and efficient removal of the occluding thrombus, either via intravenous thrombolysis or via endovascular thrombectomy. Recanalization, however, is not always successful and factors contributing to failure are not completely under- stood. Although the occluding thrombus is the primary target of acute treatment, little is known about its internal organization and composi- tion. The aim of this study, therefore, was to better understand the inter- nal organization of ischemic stroke thrombi on a molecular and cellular level. A total of 188 thrombi were collected from endovascularly treated ischemic stroke patients and analyzed histologically for fibrin, red blood cells (RBC), von Willebrand factor (vWF), platelets, leukocytes and DNA, using bright field and fluorescence microscopy. Our results show that stroke thrombi are composed of two main types of areas: RBC-rich areas and platelet-rich areas. RBC-rich areas have limited complexity as they consist of RBC that are entangled in a meshwork of thin fibrin. In con- trast, platelet-rich areas are characterized by dense fibrin structures aligned with vWF and abundant amounts of leukocytes and DNA that accumulate around and in these platelet-rich areas. These findings are important to better understand why platelet-rich thrombi are resistant to thrombolysis and difficult to retrieve via thrombectomy, and can guide further improvements of acute ischemic stroke therapy.
Introduction
Ischemic stroke is mainly caused by a thrombus that is occluding one or multiple arteries in the brain. As a consequence of the impaired cerebral blood flow, irre- versible damage occurs in the associated brain tissue. Currently, only two US Food and Drug Administration (FDA)-approved treatment regimens are available to remove the thrombus and thus recanalize the occluded blood vessel in stroke patients: (i) pharmacological thrombolysis using recombinant tissue plasminogen activator (rt-PA), which promotes degradation of fibrin in the thrombus; and (ii) mechanical removal of the thrombus via endovascular thrombectomy.
Despite recent advances, efficient recanalization in ischemic stroke patients remains a challenge. rt-PA can only be administered within the first 4.5 hours after the onset of stroke symptoms due to the risk of cerebral bleeding when treatment is delayed. As a consequence, rt-PA treatment is available to less than 15% of patients in most European countries.1 Strikingly, even in patients who receive rt-PA, more than half fail to respond to the drug.2,3 Factors contributing to this so-called rt-PA resistance are not well understood, but size and characteristics of the throm- bus itself are thought to play an important role. As of 2015, several positive trials
Correspondence:
SIMON F. DE MEYER
simon.demeyer@kuleuven.be
Received: February 22, 2019. Accepted: April 24, 2019. Pre-published: May 12, 2019.
doi:10.3324/haematol.2019.219881
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/2/498
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