Thrombin Generation Thresholds for Coagulation Initiation under Flow

Abstract

In veins, clotting initiation displays a threshold response to flow intensity and injury size. Mathematical models can provide insights into the conditions leading to clot growth initiation under flow for specific subjects. However, it is hard to determine the thrombin generation curves that favor coagulation initiation in a fast manner, especially when considering a wide range of conditions related to flow and injury size. In this work, we propose to address this challenge by using a neural network model trained with the numerical simulations of a validated 2D model for clot formation. Our surrogate model approximates the results of the 2D simulations, reaching an accuracy of 94% on the test dataset. We used the trained artificial neural network to determine the threshold for thrombin generation parameters that alter the coagulation initiation response under varying flow speed and injury size conditions. Our model predictions show that increased levels of the endogenous thrombin potential (ETP) and peak thrombin concentration increase the likelihood of coagulation initiation, while an elevated time to peak decreases coagulation. The lag time has a small effect on coagulation initiation, especially when the injury size is small. Our surrogate model can be considered as a proof-of-concept of a tool that can be deployed to estimate the risk of bleeding in specific patients based on their Thrombin Generation Assay results.

Intraplatelet Calcium Signaling Regulates Thrombus Growth under Flow: Insights from a Multiscale Model

“…The consistency of the model with experimental observations makes it suitable for systems biology studies that investigate the mechanisms regulating arterial thrombosis at the intracellular and bloodstream scales. After further validation, our framework can be deployed as a decision-making tool using techniques such as machine learning [70,71].…”