Mathematical models of fibrin polymerization: past, present, and future

Nelson, Anna C.; Kelley, Michael A.; Haynes, Laura M.; Leiderman, Karin

doi:10.1016/j.cobme.2021.100350

Cited by 7 publications

(4 citation statements)

References 60 publications

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“…This is one of just a few mathematical models that exist of fibrin polymerization [ 56 ] and, to our knowledge, the only one that considers γ ′ fibrinogen. Even though this mathematical model has its limitations, it has provided an experimentally testable idea and a new avenue of inquiry with respect to the dual role of thrombin- γ ′ binding.…”

Section: Discussionmentioning

confidence: 99%

Mathematical modeling to understand the role of bivalent thrombin-fibrin binding during polymerization

Kelley

Leiderman

2022

PLoS Comput Biol

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Thrombin is an enzyme produced during blood coagulation that is crucial to the formation of a stable clot. Thrombin cleaves soluble fibrinogen into fibrin, which polymerizes and forms an insoluble, stabilizing gel around the growing clot. A small fraction of circulating fibrinogen is the variant γA/γ′, which has been associated with high-affinity thrombin binding and implicated as a risk factor for myocardial infarctions, deep vein thrombosis, and coronary artery disease. Thrombin is also known to be strongly sequestered by polymerized fibrin for extended periods of time in a way that is partially regulated by γA/γ′. However, the role of γA/γ′-thrombin interactions during fibrin polymerization is not fully understood. Here, we present a mathematical model of fibrin polymerization that considered the interactions between thrombin, fibrinogen, and fibrin, including those with γA/γ′. In our model, bivalent thrombin-fibrin binding greatly increased thrombin residency times and allowed for thrombin-trapping during fibrin polymerization. Results from the model showed that early in fibrin polymerization, γ′ binding to thrombin served to localize the thrombin to the fibrin(ogen), which effectively enhanced the enzymatic conversion of fibrinogen to fibrin. When all the fibrin was fully generated, however, the fibrin-thrombin binding persisted but the effect of fibrin on thrombin switched quickly to serve as a sink, essentially removing all free thrombin from the system. This dual role for γ′-thrombin binding during polymerization led to a paradoxical decrease in trapped thrombin as the amount of γ′ was increased. The model highlighted biochemical and biophysical roles for fibrin-thrombin interactions during polymerization and agreed well with experimental observations.

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Section: Discussionmentioning

confidence: 99%

Mathematical modeling to understand the role of bivalent thrombin-fibrin binding during polymerization

Kelley

Leiderman

2022

PLoS Comput Biol

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“…Studies include rate kinetics-based models of the polymerization process [ 66 ]; interplay of fibrin gel formation with coagulation and flow [ 67 ]; and models of fibrin-thrombin interaction in polymerized gels [ 68 ]. A detailed review on state-of-the-art fibrin polymerization models has been presented previously [ 69 ].…”

Section: State-of-art Modeling Of Platelet-based Thrombosismentioning

confidence: 99%

Decoding thrombosis through code: a review of computational models

Grande Gutiérrez,

Mukherjee,

Bark

2024

Journal of Thrombosis and Haemostasis

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“…In contrast to device-related thrombosis modeling, a vast amount of work has been performed to understand fibrin formation dynamics due to a blood vessel injury. The modeling approaches range from kinetic pathway simulations of fibrin gel formation with ordinary differential equations [30][31][32] to complex gelation models that include blood flow interactions [33][34][35][36], as highlighted in a recent review by Nelson et al [37].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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 partial 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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Mathematical models of fibrin polymerization: past, present, and future

Cited by 7 publications

References 60 publications

Mathematical modeling to understand the role of bivalent thrombin-fibrin binding during polymerization

Mathematical modeling to understand the role of bivalent thrombin-fibrin binding during polymerization

Decoding thrombosis through code: a review of computational models

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

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