A Continuum Model for the Unfolding of von Willebrand Factor

Zhussupbekov, Mansur; Rojano, Rodrigo Méndez; Wu, Wei‐Tao; Massoudi, Mehrdad; Antaki, James F.

doi:10.1007/s10439-021-02845-5

Cited by 15 publications

(12 citation statements)

References 78 publications

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“…When the hydrodynamic and mechanical stresses are low, the multimers attain a compact (collapsed) conformation because of effective interdomain attractions 76 . Above a critical shear stress, the vWF free in flow would elongate and tumble, and it would extend in elongational flow 41 , 74 . Since such changes were not modeled in this study, the hydrodynamic radius was used for computations.…”

Section: Methodsmentioning

confidence: 99%

“…The use of a power law model to describe the vWF deformation appears to be justified because in these cases, where stresses affect the properties of a material, the effect depends on the duration of the stress application and the level of stress. In addition, prior research with vWF degradation with time, for example Zhussupbekov et al 41 and Kania et al 2 , have indicated that a power law model applies for the unfolding of vWF under stress. Indirect evidence that a power law applies for the change in protein conformation vs time and shear rate is also offered in Heidari et al 42 , where a normalized radius of gyration of the vWF was plotted as a function of the product of shear rate and a characteristic time.…”

Section: Introductionmentioning

confidence: 99%

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Distribution and history of extensional stresses on vWF surrogate molecules in turbulent flow

Pham

Feher

Nguyen

et al. 2022

Sci Rep

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The configuration of proteins is critical for their biochemical behavior. Mechanical stresses that act on them can affect their behavior leading to the development of decease. The von Willebrand factor (vWF) protein circulating with the blood loses its efficacy when it undergoes non-physiological hemodynamic stresses. While often overlooked, extensional stresses can affect the structure of vWF at much lower stress levels than shear stresses. The statistical distribution of extensional stress as it applies on models of the vWF molecule within turbulent flow was examined here. The stress on the molecules of the protein was calculated with computations that utilized a Lagrangian approach for the determination of the molecule trajectories in the flow filed. The history of the stresses on the proteins was also calculated. Two different flow fields were considered as models of typical flows in cardiovascular mechanical devises, one was a Poiseuille flow and the other was a Poiseuille–Couette flow field. The data showed that the distribution of stresses is important for the design of blood flow devices because the average stress can be below the critical value for protein damage, but tails of the distribution can be outside the critical stress regime.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Distribution and history of extensional stresses on vWF surrogate molecules in turbulent flow

Pham

Feher

Nguyen

et al. 2022

Sci Rep

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“…More recently, elongational flow has been a valuable tool in validating experimental results for computational modeling of macromolecules like DNA [16]. Perkins et al examined individual molecules of fluorescently labeled DNA in an extensional flow to learn about polymer dynamics [17] while several recent studies have examined unfolding of the von Willebrand Factor (vWF) and flow-induced aggregation [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Elongational Stresses and Cells

Foster

Papavassiliou

O’Rear

2021

Cells

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Fluid forces and their effects on cells have been researched for quite some time, especially in the realm of biology and medicine. Shear forces have been the primary emphasis, often attributed as being the main source of cell deformation/damage in devices like prosthetic heart valves and artificial organs. Less well understood and studied are extensional stresses which are often found in such devices, in bioreactors, and in normal blood circulation. Several microfluidic channels utilizing hyperbolic, abrupt, or tapered constrictions and cross-flow geometries, have been used to isolate the effects of extensional flow. Under such flow cell deformations, erythrocytes, leukocytes, and a variety of other cell types have been examined. Results suggest that extensional stresses cause larger deformation than shear stresses of the same magnitude. This has further implications in assessing cell injury from mechanical forces in artificial organs and bioreactors. The cells’ greater sensitivity to extensional stress has found utility in mechanophenotyping devices, which have been successfully used to identify pathologies that affect cell deformability. Further application outside of biology includes disrupting cells for increased food product stability and harvesting macromolecules for biofuel. The effects of extensional stresses on cells remains an area meriting further study.

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“…The reaction term for vWF c and vWF s is then obtained by multiplying the reaction rates previously described by the concentration of this species following the law of mass action. A detailed validation of the vWF‐thrombosis model is provided in Zhussupbekov et al 41 for multiple academic simple flow configurations and complex in‐vitro clotting scenarios.…”

Section: Methodsmentioning

confidence: 99%

Uncertainty quantification of a thrombosis model considering the clotting assay PFA‐100®

Rojano

Zhussupbekov

Antaki

et al. 2022

Numer Methods Biomed Eng

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Mathematical models of thrombosis are currently used to study clinical scenarios of pathological thrombus formation. As these models become more complex to predict thrombus formation dynamics high computational cost must be alleviated and inherent uncertainties must be assessed. Evaluating model uncertainties allows to increase the confidence in model predictions and identify avenues of improvement for both thrombosis modeling and anti‐platelet therapies. In this work, an uncertainty quantification analysis of a multi‐constituent thrombosis model is performed considering a common assay for platelet function (PFA‐100®). The analysis is facilitated thanks to time‐evolving polynomial chaos expansions used as a parametric surrogate for the full thrombosis model considering two quantities of interest; namely, thrombus volume and occlusion percentage. The surrogate is thoroughly validated and provides a straightforward access to a global sensitivity analysis via computation of Sobol' coefficients. Six out of 15 parameters linked to thrombus consitution, vWF activity, and platelet adhesion dynamics were found to be most influential in the simulation variability considering only individual effects; while parameter interactions are highlighted when considering the total Sobol' indices. The influential parameters are related to thrombus constitution, vWF activity, and platelet to platelet adhesion dynamics. The surrogate model allowed to predict realistic PFA‐100® closure times of 300,000 virtual cases that followed the trends observed in clinical data. The current methodology could be used including common anti‐platelet therapies to identify scenarios that preserve the hematological balance.

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A Continuum Model for the Unfolding of von Willebrand Factor

Cited by 15 publications

References 78 publications

Distribution and history of extensional stresses on vWF surrogate molecules in turbulent flow

Distribution and history of extensional stresses on vWF surrogate molecules in turbulent flow

Elongational Stresses and Cells

Uncertainty quantification of a thrombosis model considering the clotting assay PFA‐100®

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