Modeling the flow behavior of blood cells and von Willebrand factor in primary hemostasis
Final Report Abstract
The blood plasma protein von Willebrand factor (VWF) is an essential component in primary hemostasis, especially at high shear rates, when platelets are not able to adhere to an injured vessel wall by themselves. It is important to investigate the behavior and function of VWF under realistic blood flow conditions, where it interacts with other blood cells and vessel walls. Even though experiments with VWF are of course essential, they often do not permit a detailed observation and analysis of involved processes and physical mechanisms. Mesoscopic simulations at the level of single proteins and cells are able to fill this gap, allowing a detailed investigation of VWF behavior in blood flow depending on various parameters. We have employed realistic simulations of blood flow to better understand the formation of VWF-platelet aggregates. The performed simulation work has led to the following main outcomes and conclusions. The model of VWF has been extended to incorporate the effect of monomer activation/deactivation for adhesion, depending on VWF stretching. This model part is essential for a realistic representation of VWF in hydrodynamic simulations. - In shear flow near walls, VWF adhesion can exhibit different states, including sticking, slipping, roll-stick motion, and rolling motion. Different adhesion states are determined by the kinetics of bonds between VWF and a surface and can represent healthy as well as dysfunctional VWF. - Monomer deactivation for adhesion plays an essential role in a reversible VWF adhesion, when shear rates are significantly reduced. A VWF whose monomers are always adhesive does not desorb from a surface. Similarly, this effect is very important for the dissociation of VWF-platelet aggregates. - Bond properties determine whether VWF-platelet aggregates are reversible (i.e. can dissociate under low shear rates) or not. A catch-bond model leads to reversible aggregates and approximates well the behavior of VWF under normal conditions. A slip-bond model results in irreversible aggregation, representing dysfunction of VWF which may occur in some VWF related diseases. - In blood flow, both platelets and VWF molecules migrate or marginate toward vessel walls, leading to their increased concentration near the wall and more efficient functioning near an injury site. - The formation of VWF-platelet aggregates primarily occurs near vessel walls, where the shear rates are highest. Additionally, an increased concentration of platelets and VWFs near the wall due to margination promotes aggregate formation. - Large enough aggregates near the wall experience hydrodynamic lift force, which drives them toward the vessel center. If aggregation is reversible, the aggregates fall apart in the regions of low shear rates near the vessel center. Otherwise, they continue to flow near the vessel center. - Reversible VWF-platelet aggregates exhibit a repeating process: (i) free platelets and VWFs marginate toward the vessel wall, (ii) VWF-platelet aggregates form near the wall, and (iii) large aggregates migrate to the vessel center and eventually get dissolved. This process then occurs cyclically. - The developed model for VWF-platelet aggregation in blood flow captures realistic and detailed behavior of VWF. Thus, it allows simulations of blood flow and coagulation on the cellular level and can be used to better understand VWF-related diseases.
Publications
- Deformation and dynamics of red blood cells in flow through cylindrical microchannels. Soft Matter, 10:4258–4267, 2014
D. A. Fedosov, M. Peltomäki, and G. Gompper
(See online at https://doi.org/10.1039/c4sm00248b) - Margination of micro- and nano-particles in blood flow and its effect on drug delivery. Sci. Rep., 4:4871, 2014
K. Müller, D. A. Fedosov, and G. Gompper
(See online at https://doi.org/10.1038/srep04871) - Multiscale modeling of blood flow: from single cells to blood rheology. Biomech. Model. Mechanobiol., 13:239–258, 2014
D. A. Fedosov, H. Noguchi, and G. Gompper
(See online at https://doi.org/10.1007/s10237-013-0497-9) - White blood cell margination in microcirculation. Soft Matter, 10:2961–2970, 2014
D. A. Fedosov and G. Gompper
(See online at https://doi.org/10.1039/c3sm52860j) - Smoothed dissipative particle dynamics with angular momentum conservation. J. Comp. Phys., 281:301–315, 2015
K. Müller, D. A. Fedosov, and G. Gompper
(See online at https://doi.org/10.1016/j.jcp.2014.10.017) - Understanding particle margination in blood flow - a step toward optimized drug delivery systems. Med. Eng. Phys., 38:2–10, 2016
K. Müller, D. A. Fedosov, and G. Gompper
(See online at https://doi.org/10.1016/j.medengphy.2015.08.009) - Margination and stretching of von Willebrand factor in the blood stream enable adhesion. Sci. Rep., 7:14278, 2017
K. Rack, V. Huck, M. Hoore, D. A. Fedosov, S. W. Schneider, and G. Gompper
(See online at https://doi.org/10.1038/s41598-017-14346-4) - Modeling the cleavage of von Willebrand factor by ADAMTS13 protease in shear flow. Med. Eng. Phys., 48:14–22, 2017
B. Huisman, M. Hoore, G. Gompper, and D. A. Fedosov
(See online at https://doi.org/10.1016/j.medengphy.2017.06.044) - Effect of spectrin network elasticity on the shapes of erythrocyte doublets. Soft Matter, 14:6278–6289, 2018
M. Hoore, F. Yaya, T. Podgorski, C. Wagner, G. Gompper, and D. A. Fedosov
(See online at https://doi.org/10.1039/c8sm00634b) - Flow-induced adhesion of shear-activated polymers to a substrate. J. Phys.: Condens. Matter, 30:064001, 2018
M. Hoore, K. Rack, D. A. Fedosov, and G. Gompper
(See online at https://doi.org/10.1088/1361-648X/aaa4d5) - Influence of particle size and shape on their margination and wall-adhesion: implications in drug delivery vehicle design across nano-to-micro scale. Nanoscale, 10:15350–15364, 2018
M. Cooley, A. Sarode, M. Hoore, D. A. Fedosov, S. Mitragotri, and A. Sen Gupta
(See online at https://doi.org/10.1039/c8nr04042g)
