Mathematical and computational modeling of device-induced thrombosis

Manning, Keefe B.; Nicoud, Franck; Shea, Susan M.

doi:10.1016/j.cobme.2021.100349

Cited by 12 publications

(10 citation statements)

References 87 publications

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“…Thrombosis in low shear conditions is characterized by a predominance of fibrin, which is the result of factor XII production stimulating the coagulation cascade [13,53]. The current work highlights the importance of considering this mechanism in devices that have large blood-contacting surface to volume ratios, that operate at low shear rate conditions (< 1000 s In the BFS configuration, the baseline platelet-based thrombosis model without fibrin formation and contact activation was not able to generate clotting in the recirculating region nor was it able to accurately represent the predominance of fibrin in the low-shear zone, as reported in the experimental results of Taylor et al [38] The present BFS results illustrate the critical role of fibrin for predicting the time course of thrombus deposition.…”

Section: Discussionmentioning

confidence: 99%

A fibrin enhanced thrombosis model for medical devices operating at low shear regimes or large surface areas

Rojano

Lai

Zhussupbekov

et al. 2022

Preprint

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Over the past decade, much of the development of computational models of device-related thrombosis has focused on platelet activity. While those models have been successful in predicting thrombus formation in medical devices operating at high shear rates (>5000 s −1), they cannot be directly applied to low-shear devices, such as blood oxygenators and catheters, where emerging information suggest that fibrin formation is the predominant mechanism of clotting and platelet activity plays a secondary role. In the current work, we augment an existing platelet-based model of thrombosis with a reduced order model of the coagulation cascade that includes contact activation of factor XII and fibrin production. To calibrate the model, we simulate a backward-facing-step flow channel that has been extensively characterized in-vitro. Next, we perform blood perfusion experiments through a microfluidic chamber mimicking a hollow fiber membrane oxygenator and validate the model against these observations. The simulation results closely match the time evolution of the thrombus height and length in the backward-facing-step experiment. Application of the model to the microfluidic hollow fiber bundle chamber capture both gross features such as the increasing clotting trend towards the outlet of the chamber, as well as finer local features such as the structure of fibrin around individual hollow fibers. Our results are in line with recent findings that suggest fibrin production through contact activation of factor XII drives the thrombus formation in medical devices operating at low shear rates with large surface area to volume ratios.

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Section: Discussionmentioning

confidence: 99%

A fibrin enhanced thrombosis model for medical devices operating at low shear regimes or large surface areas

Rojano

Lai

Zhussupbekov

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…ADP follows a convection-diffusion-reaction equation, and is released when platelets are activated, as in Equation (7), where D ADP is the diffusivity of ADP, and R ADP is the amount of ADP released per activated platelet.…”

Section: Taylor Model and Modifications From Yang Et Almentioning

confidence: 99%

“…The need to better understand the processes of T&TE in blood-contacting devices makes in-silico models attractive, as a much richer understanding of the localized environment is possible including stresses exerted on a blood clot, local concentrations of procoagulant species, and high-resolution flow field data, though challenges remain including a disconnect between physiological and numerical timescales, experimental validation and incorporating pathologies among others. 7 Modern in-silico T&TE models are increasingly computationally affordable, and are being used in device-specific simulations to inform thrombus risk, 8 to investigate thrombolysis in strokes, 9 and to predict venous thrombosis. 10 Fogelson and Guy 11 proposed a single-scale model based on conservation equations for resting and activated platelets, a generic activator chemical taking the place of the coagulation cascade, and viscoelastic constitutive equations for a cohesive-link tensor and a cohesive-link density.…”

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confidence: 99%

Toward modeling thrombosis and thromboembolism in laminar and turbulent flow regimes

Tobin

Manning

2022

Numer Methods Biomed Eng

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Thrombosis and thromboembolism are deadly risk factors in blood-contacting biomedical devices, and in-silico models of thrombosis are attractive tools to understand the mechanics of these processes, though the simulation of thromboembolism remains underdeveloped. The purpose of this study is to modify an existing computational thrombosis model to allow for thromboembolism and to investigate the behavior of the modified model at a range of flow rates.The new and existing models are observed to lead to similar predictions of thrombosis in a canonical backward-facing step geometry across flow rates, and neither model predicts thrombosis in a turbulent flow. Simulations are performed by increasing flow rates in the case of a clot formed at lower flow to induce embolization. While embolization is observed, most of the clot breakdown is by shear rather than by breakup and subsequent transport of clotted material, and further work is required in the formulation and validation of embolization. This model provides a framework to further investigate thromboembolization.

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“…The thrombosis model used in this study is one of the most realistic models up to-date for medical devices. 47 In the following we will therefore put aside the model uncertainty in terms of its structure, complexity and underlying numerical algorithmic and we will focus only on physical parametric uncertainty. The model involves a total of 68 parameters (diffusion coefficients, reaction rates, biochemical concentrations, viscosity, density, etc).…”

Section: Identification and Modeling Of Random Sourcesmentioning

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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Mathematical and computational modeling of device-induced thrombosis

Cited by 12 publications

References 87 publications

A fibrin enhanced thrombosis model for medical devices operating at low shear regimes or large surface areas

A fibrin enhanced thrombosis model for medical devices operating at low shear regimes or large surface areas

Toward modeling thrombosis and thromboembolism in laminar and turbulent flow regimes

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

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