clazosentan and Thrombosis

Patients undergoing neurosurgical clipping or endovascular coiling of a ruptured aneurysm may differ in their risk of vasospasm.. Because clot clearance affects vasospasm, we tested the hypothesis that clot clearance differs in patients depending on method of aneurysm treatment.. Exploratory analysis was performed on 413 patients from CONSCIOUS-1, a prospective randomized trial of clazosentan for the prevention of angiographic vasospasm in patients with aneurysmal subarachnoid hemorrhage (SAH). Clot clearance was measured by change in Hijdra score between baseline computed tomography and one performed 24 to 48 hours after aneurysm treatment. Angiographic vasospasm was assessed by the use of catheter angiography 7 to 11 days after SAH, and delayed ischemic neurological deficit (DIND) was determined clinically. Extended Glasgow Outcome Score (GOSE) was assessed 3 months after SAH, and poor outcome was defined as death, vegetative state, or severe disability. Multivariable ordinal and binary logistic regression were used.. There was no significant difference in the rate of clot clearance between patients undergoing clipping or coiling (P = .56). Coiling was independently associated with decreased severity of angiographic vasospasm (odds ratio [OR] 0.53, 95% confidence interval [CI] 0.33-0.86), but not with DIND or GOSE. Greater clot clearance decreased the risk of severe angiographic vasospasm (OR 0.86, 95% CI 0.81-0.91), whereas higher baseline Hijdra score predicted increased angiographic vasospasm (OR 1.17, 95% CI 1.11-1.23) and poor GOSE (OR 1.09, 95% CI 1.04-1.14).. Aneurysm coiling and increased clot clearance were independently associated with decreased severity of angiographic vasospasm in multivariate analysis, although no differences in clot clearance were seen between coiled and clipped patients.

Topics: Adult; Angiography; Dioxanes; Endovascular Procedures; Female; Humans; Male; Middle Aged; Neurologic Examination; Prospective Studies; Pyridines; Pyrimidines; Receptor, Endothelin A; Retrospective Studies; Subarachnoid Hemorrhage; Sulfonamides; Surgical Instruments; Tetrazoles; Thrombosis; Time Factors; Tomography, X-Ray Computed; Ultrasonography, Doppler, Transcranial; Vasospasm, Intracranial

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.

Topics: Analysis of Variance; Animals; Cerebral Arteries; Dioxanes; Disease Models, Animal; Disease Progression; Drug Delivery Systems; Erythrocytes; Fibrinolytic Agents; Glycophorins; Male; Mice; Mice, Inbred C57BL; Pyridines; Pyrimidines; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Thrombosis; Time Factors; Urokinase-Type Plasminogen Activator