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Percutaneous catheter pumps are intraventricular temporary mechanical circulatory support (MCS) devices that are positioned across the aortic valve into the left ventricle (LV) and provide continuous antegrade blood flow from the LV into the ascending aorta (AA). MCS devices are most often computationally evaluated as isolated devices subject to idealized steady-state blood flow conditions. In clinical practice, MCS devices operate connected to or within diseased pulsatile native hearts and are often complicated by hemocompatibility related adverse events such as stroke, bleeding, and thrombosis. Whereas aspects of the human circulation are increasingly being simulated via computational methods, the precise interplay of pulsatile LV hemodynamics with MCS pump hemocompatibility remains mostly unknown and not well characterized. Technologies are rapidly converging such that next-generation MCS devices will soon be evaluated in virtual physiological environments that increasingly mimic clinical settings. The purpose of this brief communication is to report results and lessons learned from an exploratory CFD simulation of hemodynamics and thrombosis for a catheter pump situated within a virtual in-vivo left heart environment., Comment: 5 pages, 3 figures

PediaFlow is a miniature mixed-flow ventricular assist device for neonates and toddlers. PediaFlow has a fully magnetically levitated rotor which improves biocompatibility, but the increased length of the rotor creates a long annular passage where fluid energy is lost. Therefore, a set of helical stator blades was proposed immediately after the impeller stage to remove the swirling flow and recover the dynamic head as static pressure. Automated computational fluid dynamics (CFD) shape optimization of the stator blades was performed to maximize pressure recovery at the operating point of 1.5 LPM and 16,000 RPM. Additionally, the effect on hemolysis and thrombogenicity was assessed using numerical modeling. The optimization algorithm favored fewer blades of greater length over a larger number of short blades. The ratio of wrap angle to axial length emerged as a key constraint to ensure the viability of a design. The best design had 2 blades and generated 73 mmHg of pressure recovery in an isolated stage. When re-introduced to the CFD simulation of the complete flow path, the added stator stage increased the pump head by 46% and improved the pump efficiency from 21.9% to 25.7% at the selected operating point. Automated CFD shape optimization combined with in silico evaluation of hemocompatibility can be an effective tool for exploring design choices and informing early development process.

Thrombosis under high-shear conditions is mediated by the mechanosensitive blood glycoprotein von Willebrand Factor (vWF). vWF unfolds in response to strong flow gradients and facilitates rapid recruitment of platelets in flowing blood. While the thrombogenic effect of vWF is well recognized, its conformational response in complex flows has largely been omitted from numerical models of thrombosis. We recently presented a continuum model for the unfolding of vWF, where we represented vWF transport and its flow-induced conformational change using convection-diffusion-reaction equations. Here, we incorporate the vWF component into our multi-constituent model of thrombosis, where the local concentration of stretched vWF amplifies the deposition rate of free-flowing platelets and reduces the shear cleaning of deposited platelets. We validate the model using three benchmarks: in vitro model of atherothrombosis, a stagnation point flow, and the PFA-100, a clinical blood test commonly used for screening for von Willebrand Disease (vWD). The simulations reproduced the key aspects of vWF-mediated thrombosis observed in these experiments, such as the thrombus location, thrombus growth dynamics, and the effect of blocking platelet-vWF interactions. The PFA-100 simulations closely matched the reported occlusion times for normal blood and several hemostatic deficiencies, namely, thrombocytopenia, vWD Type 1, and vWD Type 3. Overall, the multi-constituent model of thrombosis presented in this work enables macro-scale 3-D simulations of thrombus formation in complex geometries over a wide range of shear rates and accounts for qualitative and quantitative hemostatic deficiencies in patient blood. The results also demonstrate the utility of the continuum model of vWF unfolding that could be adapted to other numerical models of thrombosis.

von Willebrand Factor is a mechano-sensitive protein circulating in blood that mediates platelet adhesion to subendothelial collagen and platelet aggregation at high shear rates. Its hemostatic function and thrombogenic effect, as well as susceptibility to enzymatic cleavage, are regulated by a conformational change from a collapsed globular state to a stretched state. Therefore, it is essential to account for the conformation of the vWF multimers when modeling vWF-mediated thrombosis or vWF degradation. We introduce a continuum model of vWF unfolding that is developed within the framework of our multi-constituent model of platelet-mediated thrombosis. The model considers two interconvertible vWF species corresponding to the collapsed and stretched conformational states. vWF unfolding takes place via two regimes: tumbling in simple shear and strong unfolding in flows with dominant extensional component. These two regimes were demonstrated in a Couette flow between parallel plates and an extensional flow in a cross-slot geometry. The vWF unfolding model was then verified in several microfluidic systems designed for inducing high-shear vWF-mediated thrombosis and screening for von Willebrand Disease. The model predicted high concentration of stretched vWF in key regions where occlusive thrombosis was observed experimentally. Strong unfolding caused by the extensional flow was limited to the center axis or middle plane of the channels, whereas vWF unfolding near the channel walls relied upon the shear tumbling mechanism. The continuum model of vWF unfolding presented in this work can be employed in numerical simulations of vWF-mediated thrombosis or vWF degradation in complex geometries. However, extending the model to 3-D arbitrary flows and turbulent flows will pose considerable challenges.

Mathematical models of thrombosis are currently used to study clinical scenarios of pathological thrombus formation. Most of these models involve inherent uncertainties that must be assessed 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 performed using a polynomial chaos expansion as a parametric surrogate for the thrombosis model. The polynomial approximation is validated and used to perform a global sensitivity analysis via computation of Sobol' coefficients. Six out of fifteen parameters were found to be influential in the simulation variability considering only individual effects. Nonetheless, parameter interactions are highlighted when considering the total Sobol' indices. In addition to the sensitivity analysis, the surrogate model was used to compute the PFA-100 closure times of 300,000 virtual cases that align well with clinical data. The current methodology could be used including common anti-platelet therapies to identify scenarios that preserve the hematological balance., Comment: 17 pages, 10 figures, 3 tables, original research article

Thromboembolic complications remain a central issue in management of patients on mechanical circulatory support. Despite the best practices employed in design and manufacturing of modern ventricular assist devices, complexity and modular nature of these systems often introduces internal steps and crevices in the flow path which can serve as nidus for thrombus formation. Thrombotic potential is influenced by multiple factors including the characteristics of the flow and surface chemistry of the biomaterial. This study explored these elements in the setting of blood flow over a micro-crevice using a multi-constituent numerical model of thrombosis. The simulations reproduced the platelet deposition patterns observed experimentally and elucidated the role of flow, shear rate, and surface chemistry in shaping the deposition. The results offer insights for design and operation of blood-contacting devices.