The role of geometry in the hemodynamics associated with stroke development in sickle cell anemia

Abstract

Sickle cell anemia (SCA) is a genetic blood disorder which affects over 4 million people globally. Though SCA is caused by a single point mutation in the hemoglobin of red blood cells, this change has devastating affects which can impact the entire human body and reduce life expectancy. Amongst the complications associated with SCA, there is a 200-fold increase in the likelihood of ischemic stroke in children and adolescents. Approximately 11.5% of individuals with SCA will develop an overt stroke before 18 years of age, and those between 2 and 8 at the greatest risk. The only method to determine stroke risk is with through transcranial Doppler and measuring blood flow in the cerebral arteries. Individuals who have a time-average maximum-mean blood velocity exceeding 200 cm/s have a significantly elevated risk of developing a stroke in the future. The objective of this thesis is to provide insight into these elevated blood velocities by identifying and validating flow-mediated mechanisms predisposing children with sickle cell anemia to strokes. Using computational fluid dynamics (CFD), we have demonstrated that individuals with SCA have elevated blood velocities, even when inlet boundary conditions matched those without SCA. This indicates geometrical differences are a cause for the elevated velocities indicative of strokes risk. In addition to these findings, individuals with SCA had increased regions of low and oscillatory shear stress, a stimulus for endothelial dysfunction and vascular remodeling. The role of geometry was further investigated using the Townes sickle cell transgenic mouse model. Through a combination of live imaging with ultrasound and corrosion casting, morphometrics were measured in the carotid and cerebral arteries of homozygous sickle (SS) and heterozygous sickle (AS) mice. SS mice were found to have significantly larger common carotid artery diameters than AS mice, and significantly larger diameters in the extracranial and intracranial portions of the ICA. Significant narrowing was also determined along ICA, decreasing by as much as 70%, such that the terminal tributaries of the MCA and ACA had no differences in size between genotypes.