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THE EFFECT OF FLOW ON MICROPARTICLE TRANSPORT AND THE ROLE OF MICROPARTICLES IN THROMBOSIS
Title
THE EFFECT OF FLOW ON MICROPARTICLE TRANSPORT AND THE ROLE OF MICROPARTICLES IN THROMBOSIS
Creator
Lee, Ying-hui
Date
2012-11-27, 2012-12
Description
Elevated monocyte/macrophage-derived microparticles (MPs) have been found to correlate with thrombotic complications. These MPs carry tissue...
Show moreElevated monocyte/macrophage-derived microparticles (MPs) have been found to correlate with thrombotic complications. These MPs carry tissue factor (TF), the principal coagulation pathway initiator, as their parental cells and expose anionic phospholipid phosphatidylserine (PS), which can promote thrombin generation and fibrin formation. During thrombus development, MPs may be delivered to the injured/dysfunctional vascular endothelium or biomaterial surfaces and influence the process of thrombosis. MPs are submicron membrane vesicles that may have increased transport and/or binding capabilities compared to platelets or other cell types due to their decreased size and their higher Brownian diffusion. MPs and their surface molecules can be delivered to surfaces, either biological or prosthetic, and alter the local environment. Little is known of the mechanisms by which MPs are transported to and impart their biological activity on surfaces, especially in blood. Such a transfer of activity will depend on the ability of MPs to be transported to the surface, the strength of adhesion of the MPs on the surface and the nature of the activity/host interaction. In the present study, physical and biological properties of MPs generated from macrophage-like cell lines by endotoxin stimulation were characterized, the transport of MPs to surface by flow was investigated, and the import biological activity on surfaces was elucidated. We observed that the deposition of MPs suspended in buffer on glass surfaces was strongly shear-dependent using a well-defined parallel plate flow chamber. The diffusivity coefficients of MPs at shear rate ranges ranging from 100 to 3200 s-1 were determined from the classical mass transport equation proposed by Leveque and the values were found to be of the same order of magnitude as predicted by Brownian xi diffusion. MPs non-specific attachment to glass was dominated by electrostatic interactions; this was verified by changing the surrounding ionic strength of the suspending solution. In addition to shear rate, red blood cells (RBCs) also influenced MP adhesion due to the complex movement of RBCs. Such movement has been shown to enhance the adhesion of platelets (1-2 micron size cells) to surfaces in flowing blood. MP lateral transport was enhanced at low concentrations of RBCs and reduced at higher concentration of RBCs. The reduction of MP deposition was due to the competition for surface binding sites between the two populations of MPs. The two types of MPs studied here, those produced by macrophages after endotoxin stimulation and those produced by RBCs during experimental preparation (repeated centrifugal washing) have the capability of nonspecific binding to artificial surfaces in a competitive manner. Finally, we demonstrated that the amount of adherent MPs on surfaces influenced fibrin formation via both a TF-dependent and a negatively charged phospholipid pathway. These findings suggest that procoagulant MPs may modulate thrombotic events under certain conditions, especially in MP-associated diseases. The knowledge of the effects of flow on MP transport and the influence of increased MPs on thrombosis may provide novel insights for the transfer of biological activity to relatively passive surfaces.
PH.D in in Biomedical Engineering, December 2012
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