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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

The unacceptably high stroke rate of HeartMate III VAD without signs of adherent pump thrombosis is hypothesized to be the result of the thrombi originating on the inflow cannula, ingesting and ejecting emboli from the VAD. Therefore, inflow cannula thrombosis has been an emerging focus. The inflow cannula of contemporary VADs, which incorporate both polished and rough regions serve as useful benchmarks to study the effects of roughness and shear on thrombogenesis. An in vitro study was conducted to emulate the micro-hemodynamic condition on a sintered inflow cannula, and to observe the deposition and detachment patterns. Together with a computational fluid dynamic tool, this study aimed to provide insight into the optimization of inflow cannula and potentially reducing adverse neurological events due to upstream thrombus.

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

Continuous-flow ventricular assist devices (VADs) have been an increasingly common, life-saving therapy for advanced heart-failure patients, but elevate the risk of thrombosis due to a combination of non-physiological hemodynamics and synthetic biomaterials. Limited work has been done to address platelet adhesion and aggregation on artificial surfaces under flow with sub-threshold concentrations of weak agonists. We perfused a blood analog containing hemoglobin-depleted red blood cells and fluorescently labeled platelets across a titanium alloy (Ti6Al4V) and zirconia-toughened alumina (ZTA) surface at shear rates of 400 and 1000 s-1. Upstream of the specimen, sub-threshold concentrations of ADP were uniformly introduced at concentrations of 0, 5, and 10 nM. Time-lapse videos of depositing platelets were recorded, and the percentage of the surface covered was quantified. Surface coverage percentages at 400 s-1and 1000 s-1were compared for each concentration of ADP and material surface combination. We observed a threshold concentration of ADP that expedites platelet deposition that is dependent on both shear and material surface chemistry. Additionally, we observed embolization when thrombus areas exceeded 300{\mu}m2, which was dependent on the combination of shear, ADP concentration, and material surface. This work is the first to simultaneously examine the three key contributing factors leading to thrombotic events. Our findings assist in considering alternative material choices constituting VADs and the need to address material reactivity in assessing antiplatelet agent tests., Comment: Disagreements with data interpretation and analysis

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.

Objective: This study illustrates the ambiguity of ROC in evaluating two classifiers of 90-day LVAD mortality. This paper also introduces the precision recall curve (PRC) as a supplemental metric that is more representative of LVAD classifiers performance in predicting the minority class. Background: In the LVAD domain, the receiver operating characteristic (ROC) is a commonly applied metric of performance of classifiers. However, ROC can provide a distorted view of classifiers ability to predict short-term mortality due to the overwhelmingly greater proportion of patients who survive, i.e. imbalanced data. Methods: This study compared the ROC and PRC for the outcome of two classifiers for 90-day LVAD mortality for 800 patients (test group) recorded in INTERMACS who received a continuous-flow LVAD between 2006 and 2016 (mean age of 59 years; 146 females vs. 654 males) in which mortality rate is only %8 at 90-day (imbalanced data). The two classifiers were HeartMate Risk Score (HMRS) and a Random Forest (RF). Results: The ROC indicates fairly good performance of RF and HRMS classifiers with Area Under Curves (AUC) of 0.77 vs. 0.63, respectively. This is in contrast with their PRC with AUC of 0.43 vs. 0.16 for RF and HRMS, respectively. The PRC for HRMS showed the precision rapidly dropped to only 10% with slightly increasing sensitivity. Conclusion: The ROC can portray an overly-optimistic performance of a classifier or risk score when applied to imbalanced data. The PRC provides better insight about the performance of a classifier by focusing on the minority class., Comment: Submitted to JACC Heart Failure

Left ventricular assist devices (LVADs) are an increasingly common therapy for patients with advanced heart failure. However, implantation of the LVAD increases the risk of stroke, infection, bleeding, and other serious adverse events (AEs). Most post-LVAD AEs studies have focused on individual AEs in isolation, neglecting the possible interrelation, or causality between AEs. This study is the first to conduct an exploratory analysis to discover common sequential chains of AEs following LVAD implantation that are correlated with important clinical outcomes. This analysis was derived from 58,575 recorded AEs for 13,192 patients in International Registry for Mechanical Circulatory Support (INTERMACS) who received a continuousflow LVAD between 2006 and 2015. The pattern mining procedure involved three main steps: (1) creating a bank of AE sequences by converting the AEs for each patient into a single, chronologically sequenced record, (2) grouping patients with similar AE sequences using hierarchical clustering, and (3) extracting temporal chains of AEs for each group of patients using Markov modeling. The mined results indicate the existence of seven groups of sequential chains of AEs, characterized by common types of AEs that occurred in a unique order. The groups were identified as: GRP1: Recurrent bleeding, GRP2: Trajectory of device malfunction & explant, GRP3: Infection, GRP4: Trajectories to transplant, GRP5: Cardiac arrhythmia, GRP6: Trajectory of neurological dysfunction & death, and GRP7: Trajectory of respiratory failure, renal dysfunction & death. These patterns of sequential post-LVAD AEs disclose potential interdependence between AEs and may aid prediction, and prevention, of subsequent AEs in future studies., Comment: "under review" IEEE Journal of Biomedical and Health Informatics

Motivated by the complex rheological behaviors observed in small/micro scale blood vessels, such as the Fahraeus effect, plasma-skimming, shear-thinning, etc., we develop a non-linear suspension model for blood. The viscosity is assumed to depend on the volume fraction (hematocrit) and the shear rate. The migration of the red blood cells (RBCs) is studied using a concentration flux equation. A parametric study with two representative problems, namely simple shear flow and a pressure driven flow demonstrate the ability of this reduced-order model to reproduce several key features of the two-fluid model (mixture theory approach), with much lower computational cost.

Thrombosis is a common complication following the surgical implantation of blood contacting devices, and is strongly influenced by the phenomenon of near-wall enrichment of platelets. This paper describes a multi-constituent continuum approach to study this phenomenon. A mixture-theory model is used to describe the motion of the plasma and the red blood cells (RBCs) and the interactions between the two components. A transport model is developed to study the influence of the RBC field on the platelets. The model is used to study blood flow in a rectangular micro-channel, a sudden expansion micro-channel, and a channel containing micro crevices (representing a practical problem encountered in most blood-wetted devices). The simulations show that in the rectangular channel the concentration of platelets near the walls is about five times higher than the concentration near the centerline of the channel. It is also noticed that in the channel with crevices, extremely a large number of platelets accumulate in the deep part of the crevices and this may serve as the nidus for thrombosis occurring in medical devices. Keywords: Platelets; Blood flow; RBCs; Micro-channel; Mixture theory; Two-fluids; Thrombosis

In this paper, we study the fully developed gravity-driven flow of granular materials between two inclined planes. We assume that the granular materials can be represented by a modified form of the second-grade fluid where the viscosity depends on the shear rate and volume fraction and the normal stress coefficients depend on the volume fraction. We also propose a new isotropic (spherical) part of the stress tensor which can be related to the compactness of the (rigid) particles. This new term ensures that the rigid solid particles cannot be compacted beyond a point, namely when the volume fraction has reached the critical/maximum packing value. The numerical results indicate that the newly proposed stress tensor has an obvious and physically meaningful effects on both the velocity and the volume fraction fields., Comment: This manuscript has been submitted to the International Journal of Non-Linear Mechanics

In this paper, we present a spatio-temporal mathematical model for simulating the formation and growth of a thrombus. Blood is treated as a multi-constituent mixture comprised of a linear fluid phase and a thrombus (solid) phase. The transport and reactions of 10 chemical and biological species are incorporated using a system of coupled convection-reaction-diffusion (CRD) equations to represent three processes in thrombus formation: initiation, propagation and stabilization. Computational fluid dynamic (CFD) simulations using the libraries of OpenFOAM were performed for two illustrative benchmark problems: in vivo thrombus growth in an injured blood vessel and in vitro thrombus deposition in micro-channels (1.5mm x 1.6mm x 0.1mm) with small crevices (125{\mu}m x 75{\mu}m and 125{\mu}m x 137{\mu}m). For both problems, the simulated thrombus deposition agreed very well with experimental observations, both spatially and temporally. Based on the success with these two benchmark problems, which have very different flow conditions and biological environments, we believe that the current model will provide useful insight into the genesis of thrombosis in blood-wetted devices, and provide a tool for the design of less thrombogenic devices., Comment: Submission planned to Biophysical Journal