Session: 07-07-03: Computational Modeling in Biomedical Applications III

Paper Number: 166205

Modeling and Probing Contracting Fibrin-Platelet Clots and Interaction With Red Blood Cells 

Contracting blood clots are active materials that play a crucial role in hemostasis and thrombosis regulation. Following injury, a sequence of biochemical and mechanical events leads to the formation of a soft plug composed of platelets and fibrin fibers. Platelets generate contractile forces that shrink the clot, modify its structure, and enhance mechanical stability. Impaired clot contraction alters volumetric, mechanical, and structural properties, contributing to severe bleeding and thrombotic disorders. Due to the complex interplay of mechanical factors governing clot contraction, its underlying mechanics and interactions with red blood cells (RBCs) remain poorly understood. A deeper understanding of clot contraction is critical for developing targeted therapies, improving medical diagnostics, and optimizing biomaterial-based wound treatments such as platelet-rich plasma (PRP), platelet-rich fibrin (PRF), and synthetic platelet-inspired materials. Our computational model provides insights into the engineering of platelet-based biomaterials, enabling the design of structures with tailored stress and stiffness profiles for enhanced wound healing.

Using an experimentally informed, physics-based, three-dimensional mesoscale computational model based on the dissipative particle dynamics (DPD), we probe the dynamic interactions among platelets, fibrin polymers, and RBCs, and examine the properties of contracted blood clots. DPD is a particle based method that uses beads representing clusters of molecules that interact via soft pairwise potentials yielding repulsive, dissipative, and random forces that conserve local momentum. The fibrin fibers, platelets, and RBCs immersed in a viscous DPD fluid are modeled using bead-spring approach. The interactions between bonded beads are defined by a harmonic bond potential. In addition, for platelets and fibrin fibers, we use a bending potential, whereas for RBCs, we use a quadratic dihedral potential.

We create the spherical fibrin clot mesh as semi-flexible bead chains interconnected at randomly distributed cross-link points via a MATLAB script that incorporates cross-linking densities determined from confocal image analysis of experimental fibrin clots. We simulate physiological platelet concentrations representative of venous and arterial clot conditions. We model individual platelets using clusters of DPD beads. At rest, platelets have disk-like shape and do not actively interact with other clot elements, while activated platelets extend filopodia that connect to random neighboring fibrin filaments and then contract. The process of filopod retraction is modelled by gradually shortening the bonds in filopod until the attached fibrin fiber reaches the platelet body. The retraction is performed in a series of small steps, and the clot is equilibrated after each retraction step. The contractile force exerted by a filopod is limited by the max force observed in single platelet contraction experiments. RBCs are modelled as a biconcave membrane filled with an internal fluid. The membrane consists of interconnected beads forming a triangular lattice. The membrane is filled with DPD fluid that severs to maintain the RBC volume.

Our simulations confirm that RBCs strongly affect clot contraction. We find that RBC retention and compaction in thrombi can be solely a result of mechanistic contraction of fibrin mesh due to platelet activity. During contraction, platelet activity generates inward motions of the fibrin mesh. The motion of fibers can be obstructed by the presence of RBCs located within the clot. When fibers encounter RBCs they push the cells towards the clot center bringing them closer to each other and increasing the cell number density. Such retention of RBCs hinders clot contraction and reduces clot contractility. Expulsion of RBCs located closer to clot outer surface results in the development of a dense fibrin shell in thrombus clots commonly observed in experiments. We systematically examined the correlation between clot contraction and RBC retention. Our simulations reveal the dependence of RBC retention on the initial clot size, which may be a relevant factor in the development of platelet-rich thrombi (white clots) and RBC-rich thrombi (red clots). Small clots (less than 5 RBC diameters) are unable to entrap RBCs and are more likely to contract to dense fibrin-platelet structures. During contraction, RBCs escape from smaller clots that have few fibrin fibers to envelope and trap RBCs. Larger clots are able to retain a significant amount of RBCs.

Our simulations identify the essential parameters and interactions that control blood clot contraction process, highlighting its dependence on platelet concentration and the initial clot size. Furthermore, our computational model can serve as a useful tool in clinically-relevant studies of hemostasis and thrombosis disorders, and post thrombotic clot lysis, deformation and breaking.

Presenting Author: Yueyi Sun Lafayette College

Presenting Author Biography: Yueyi (Diana) Sun
Assistant Professor (tenure-track)
Mechanical Engineering Department, Lafayette College
sunyue@lafayette.edu

EDUCATION
M.S. & Ph.D. Mechanical Engineering
Georgia Institute of Technology, Atlanta, GA August 2016 - June 2023
Advisor: Dr. Alexander Alexeev
Major area: computational fluid dynamics
Minor area: Polymeric and biological materials
Dissertation: Probing and Mesoscale Modeling of Blood Clot Contraction
B.S. Mechanical Engineering
Georgia Institute of Technology, Atlanta, GA August 2013 - June 2016


PUBLICATIONS
Journal Articles
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Kim D., Magasinski A., Sun Y., Wang B., Aashray Narla, Seung-Hun Lee, Hana Yoo et al. Overcoming the Energy vs Power Dilemma in Commercial Li-Ion Batteries via Sparse Channel Engineering. ACS Energy Letters 9, no. 10 (2024): 5056-5063. Doi:10.1021
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Sun, Y., Le. H., Lam, W.A. and Alexeev, A. Probing interactions of red blood cells and contracting fibrin platelet clots. Biophysical J. 2023 Nov 7;122(21):4123-4134. doi: 10.1016/j.bpj.2023.08.009.
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Cover art, receive editor review article
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Sun, Y., Oshinowo, O., Myers, D.R., Lam, W.A. and Alexeev, A. Resolving the missing link between single platelet force and clot contractile force. iScience 25.1 (2022): 103690
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Sun, Y., Myers, D.R., Nikolov, S.V., Oshinowo, O., Baek, J., Bowie, S.M., Lambert, T.P., Woods, E., Sakurai, Y., Lam, W.A. and Alexeev, A. Platelet heterogeneity enhances blood clot volumetric contraction: an example of asynchrono-mechanical amplification. Biomaterials 274 (2021): 120828

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