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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
neuroscience
Microthrombosis after experimental subarachnoid hemorrhage: Time course and effect of red blood cell-bound thrombin-activated pro-urokinase and clazosentan
Experimental Neurology, Volume 233, No. 1, Year 2012
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Description
Delayed cerebral ischemia (DCI) is a significant cause of morbidity and mortality for patients surviving the rupture of an intracranial aneurysm. Despite an association between vasospasm and DCI, thrombosis and thromboembolism may also contribute to DCI. In this study we investigate the time course of intravascular microclot formation after experimental subarachnoid hemorrhage (SAH) and assess the effects of the following two drugs on microclot burden: mutant thrombin-activated urokinase-type plasminogen activator (scFv/uPA-T), which is bound to red blood cells for use as a thromboprophylactic agent, and clazosentan, an endothelin antagonist. In the first study, adult male C57BL/6 mice were sacrificed at 24 (n= 5), 48 (n= 6), 72 (n=8), and 96 (n= 3) hours after SAH induced by filament perforation of the anterior cerebral artery. Sham animals (n= 5) underwent filament insertion without puncture. In the second study, animals received scFv/uPA-T (n= 5) 3. hours after hemorrhage, clazosentan (n= 5) by bolus and subcutaneous pump after SAH just prior to skin closure, or a combination of scFv/uPA-T and clazosentan ( n= 4). Control (n= 6) and sham (n= 5) animals received saline alone. All animals were sacrificed at 48. hours and underwent intra-cardiac perfusion with 4% paraformaldehyde. The brains were then extracted and sliced coronally on a cryostat and processed for immunohistochemistry. An antibody recognizing thrombin-anti-thrombin complexes was used to detect microclots on coronal slices. Microclot burden was calculated for each animal and compared among groups. Following SAH, positive anti-thrombin staining was detected bilaterally in the following brain regions, in order of decreasing frequency: cortex; hippocampus; hypothalamus; basal ganglia. Few microclots were found in the shams. Microclot burden peaked at 48. hours and then decreased gradually. Animals receiving scFv/uPA-T and scFv/uPA-T. +. clazosentan had a lower microclot burden than controls, whereas animals receiving clazosentan alone had a higher microclot burden (p<. 0.005). The overall mortality rate in the time course study was 40%; mortality was highest among control animals in the second study. Intravascular microclots form in a delayed fashion after experimental SAH. Microclots may be safely reduced using a novel form of thromboprophylaxis provided by RBC-targeted scFv/uPA-T and represent a potential target for therapeutic intervention in the treatment of DCI. © 2011.
Authors & Co-Authors
Pisapia, Jared M.
United States, Philadelphia
Hospital of the University of Pennsylvania
Xu, Xiangsheng
United States, Philadelphia
Hospital of the University of Pennsylvania
Kelly, Jane
United States, Philadelphia
Hospital of the University of Pennsylvania
Yeung, Jamie
United States, Philadelphia
Hospital of the University of Pennsylvania
Carrion, Geneive
United States, Philadelphia
Hospital of the University of Pennsylvania
Tong, Huaiyu
China, Beijing
General Hospital of People's Liberation Army
Meghan, Sudha
United States, Philadelphia
Hospital of the University of Pennsylvania
El-Falaky, Omar M.
Egypt, Cairo
Faculty of Medicine
Grady, M. Sean
United States, Philadelphia
Hospital of the University of Pennsylvania
Smith, Douglas H.
United States, Philadelphia
Hospital of the University of Pennsylvania
Zaitsev, Sergei
United States, Philadelphia
University of Pennsylvania Perelman School of Medicine
Muzykantov, Vladimir R.
United States, Philadelphia
University of Pennsylvania Perelman School of Medicine
Stiefel, Michael F.
United States, Valhalla
Westchester Medical Center
Stein, Sherman C.
United States, Philadelphia
Hospital of the University of Pennsylvania
Statistics
Citations: 69
Authors: 14
Affiliations: 5
Identifiers
Doi:
10.1016/j.expneurol.2011.10.029
ISSN:
00144886
Research Areas
Noncommunicable Diseases
Study Design
Randomised Control Trial
Participants Gender
Male