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Pisapia, J. M., X. Xu, J. Kelly, J. Yeung, G. Carrion, H. Tong, S. Meghan, O. M. El-Falaky, S. M. Grady, D. H. Smith, et al., "Microthrombosis after experimental subarachnoid hemorrhage: time course and effect of red blood cell-bound thrombin-activated pro-urokinase and clazosentan.", Experimental neurology, vol. 233, issue 1, pp. 357-63, 2012 Jan. Abstract

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.

Stein, S. C., P. Georgoff, S. Meghan, K. L. Mirza, and O. M. El Falaky, "Relationship of aggressive monitoring and treatment to improved outcomes in severe traumatic brain injury.", Journal of neurosurgery, vol. 112, issue 5, pp. 1105-12, 2010 May. Abstract

OBJECT: Despite being common practice for decades and being recommended by national guidelines, aggressive monitoring and treatment of patients with severe traumatic brain injury (TBI) have not been supported by convincing evidence.

METHODS: The authors reviewed trials and case series reported after 1970 in which patients were treated for severe closed TBI, and mortality rates and favorable outcomes at 6 months after injury were analyzed. The patient groups were divided into those with and without intracranial pressure (ICP) monitoring and intensive therapy, and the authors performed a meta-analysis to assess the effects of treatment intensity on outcome.

RESULTS: Although the mortality rate fell during the years reviewed, it was consistently approximately 12% lower among patients in the intense treatment group (p < 0.001). Favorable outcomes did not change significantly over time, and were 6% higher among the aggressively treated patients (p = 0.0105).

CONCLUSIONS: Aggressive ICP monitoring and treatment of patients with severe TBI is associated with a statistically significant improvement in outcome. This improvement occurs independently of temporal effects.