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

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.

Timelines of adverse event journeys of LVAD patients.

OBJECTIVE: The INTERMACS Events data set contains an expansive collection of temporal evidence of the course of adverse events (AEs) of >15 000 patients that have received a left ventricular assist device (LVAD). The chronology of AEs may contain insightful information of the "AE journeys" of LVAD patients. The purpose of this study is to investigate the timelines of AEs within the INTERMACS database. METHODS: Descriptive statistics were applied to 86 912 recorded AEs of 15 820 patients with a continuous flow-LVAD between 2008 to 2016, extracted from INTERMACS registry. The characteristics of the timelines of AE journeys were investigated by posing six descriptive research questions. RESULTS: The analysis revealed several time-related characteristics and patterns of the AE journey after LVAD including the most common time of occurrences of AEs after surgery, duration of AEs journeys, the time of first and last AEs, and the time gaps between AEs. CONCLUSION: The INTERMACS Event dataset is a valuable resource for research about the timeline of AE journeys of patients who received an LVAD. It is necessary for future studies to first explore and consider the time-related characteristics of the data set such as diversity and sparsity to effectively choose an appropriate scope of time and time granularity and to acknowledge potential challenges.

The roles of sub-micron and microscale roughness on shear-driven thrombosis on titanium alloy surfaces.

BACKGROUND: Continuous-flow ventricular assist devices (cfVADs) are implanted in patients with end-stage heart failure to assist with blood circulation. However, VAD implantation is associated with dangerous thrombotic complications. Our goal was to determine the impact of micron and sub-micron scale Ti6Al4V surface roughness on adherent platelet aggregate properties under clinically relevant shear rates. METHODS: We used fluorescence microscopy to visualize platelets in real time as they adhered to Ti6Al4V coupons of varying degrees of roughness, including a smooth control, in microfluidic channels and quantified deposition using an image processing algorithm. We systematically characterized roughness using spatial frequencies to generalize results for more blood-biomaterial contact applications. RESULTS: We observed that on the control and sub-micron rough surfaces, at 1000 s-1 , platelets adhered uniformly on the surface. At 2000 s-1 , we observed small and stably adherent platelet aggregates. At 5500 s-1 , platelet aggregates were large, unstable and interconnected via fibrillar structures. On a surface with micron-scale roughness features, at all three shear rates, platelets deposited in the troughs of the roughened surface, and formed aggregates. Thrombus height at 2000 s-1 and 5500 s-1 was greatest on the roughest surface and lowest on the mirror-finished surface, as indicated by the mean fluorescence intensity. CONCLUSIONS: These results demonstrated that at high shear rates, thrombi form regardless of surface topography at the scales applied. At lower shear rates, micron-scale surface features cause thrombus formation, whereas submicron features result in innocuous platelet adhesion. These findings have implications for manufacturing costs and other considerations.

von Willebrand factor unfolding mediates platelet deposition in a model of high-shear thrombosis.

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, this multi-constituent model of thrombosis enables macro-scale 3D 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.

Multi-constituent simulation of thrombus formation at LVAD inlet cannula connection: Importance of Virchow's triad.

As pump thrombosis is reduced in current-generation ventricular assist devices (VAD), adverse events such as bleeding or stroke remain at unacceptable rates. Thrombosis around the VAD inlet cannula (IC) has been highlighted as a possible source of stroke events. Recent computational fluid dynamics (CFD) studies have attempted to characterize the thrombosis risk of different IC-ventricle configurations. However, purely CFD simulations relate thrombosis risk to ad hoc criteria based on flow characteristics, with little consideration of biochemical factors. This study investigates the genesis of IC thrombosis including two elements of the Virchow's triad: endothelial injury and hypercoagulability. To this end a multi-scale thrombosis simulation that includes platelet activity and coagulation reactions was performed. Our results show significant thrombin formation in stagnation regions (|u| < 0.005 m/s) close to the IC wall. In addition, high shear-mediated platelet activation was observed over the leading-edge tip of the cannula. The current study reveals the importance of biochemical factors to the genesis of thrombosis at the ventricular-cannula junction in a perioperative state. This study is a first step toward the long-term objective of including clinically relevant pharmacological kinetics such as heparin or aspirin in simulations of inflow cannula thrombosis.

High-speed visualization of ingested, ejected, adherent, and disintegrated thrombus in contemporary ventricular assist devices.

Biocompatibility of ventricular assist devices (VADs) has been steadily improving, yet the rate of neurological events remains unacceptably high. Recent speculation for elevated stroke rates centers on ingestion of thrombi originating upstream of the pump, such as in the ventricle or left atrial appendage. These thrombi may be ejected by the VAD or become deposited within the blood flow pathway, presenting serious complications to the patient. This study was performed to visualize and quantify the degree of disruption, adherence, and disintegration of thrombi that are ingested by the three most implanted VADs: the HeartMate II, HeartMate 3, and HVAD. Clot analogs of varying microstructure compositions (red, white) and sizes (0.5, 1, 2 cm3 ) were synthesized in vitro based on clinical explant data. These were introduced individually into an in vitro flow loop with a transparent replica of the HMII, HM3, and HVAD operated at nominal steady flow (2.3-4.0 L/min). High-speed videography (up to 10 000 fps) revealed the ingestion, disruption, ejection, and adherence of thrombus fragments. Thromboemboli of varying compositions and sizes were observed mechanically attaching to components in all 3 VAD models. In some instances, ingested thrombi physically obstructed portions of the blood flow path; 18% (3 of 17 total) of red thrombi adhered to the inflow straightener of the transparent HMII. In the HVAD model, fewer than 4% of clots were adherent or trapped within the pump, irrespective of microstructure or initial volume. In comparison, 100% (4 of 4 total) of 1-cm3 white (fibrin) clots became lodged within the transparent HM3 while, in contrast, less than 5% of macerated red clots (3 of 63 total) of the same volume were adherent inside the pump. A significant proportion of ingested thrombi were macerated into infinitesimal fragments; 84% and 74% of 2-cm3 red thrombi in the HVAD and HM3 models, respectively, were found to have disintegrated upon ingestion. However, large emboli were also discharged from both centrifugal VADs; these fragments, ranging from 0.01 to 0.29 cm3 regardless of microstructure and original volume, may be capable of occluding an intracranial vessel. Therefore, ingested thrombus may explain, in part, elevated stroke rates in contemporary blood pumps in the absence of adherent pump thrombosis.

Simulation of thrombosis in a stenotic microchannel: The effects of vWF-enhanced shear activation of platelets.

This study was undertaken to develop a numerical/computational simulation of von Willebrand Factor (vWF) - mediated platelet shear activation and deposition in an idealized stenosis. Blood is treated as a multi-constituent mixture comprised of a linear fluid component and a porous solid component (thrombus). Chemical and biological species involved in coagulation are modeled using a system of coupled convection-reaction-diffusion (CRD) equations. This study considers the cumulative effect of shear stress (history) on platelet activation. The vWF activity is modeled as an enhancement function for the shear stress accumulation and is related to the experimentally-observed unfolding rate of vWF. A series of simulations were performed in an idealized stenosis in which the predicted platelets deposition agreed well with previous experimental observations spatially and temporally, including the reduction of platelet deposition with decreasing expansion angle. Further simulation indicated a direct relationship between vWF-mediated platelet deposition and degree of stenosis. Based on the success with these benchmark simulations, it is hoped that the model presented here may provide additional insight into vWF-mediated thrombosis and prove useful for the development of more hemo-compatible blood-wetted devices in the future.

Simulation of blood flow in a sudden expansion channel and a coronary artery.

In this paper, we numerically simulate the flow of blood in two benchmark problems: the flow in a sudden expansion channel and the flow through an idealized curved coronary artery with pulsatile inlet velocity. Blood is modeled as a suspension (a non-linear complex fluid) and the movement of the red blood cell (RBCs) is modeled by using a concentration flux equation. The viscosity of blood is obtained from experimental data. In the sudden expansion flow, the predicted velocity profiles for two different Reynolds numbers (based on the inlet velocity) agree well with the available experiments; furthermore, the numerical results also show that after the sudden expansion there exists a RBCs depletion region. For the second problem, the idealized curved coronary artery, it is found that the RBCs move towards and concentrate near the inner surface where the viscosity is higher and the shear stress lower; this phenomenon may be related to the atherosclerotic plaque formation which usually occurs on the inside surface of the arteries.

A non-linear fluid suspension model for blood flow.

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.

Experimental Study of Micro-Scale Taylor Vortices Within a Co-Axial Mixed-Flow Blood Pump.

Taylor vortices in a miniature mixed-flow rotodynamic blood pump were investigated using micro-scale particle image velocimetry (µ-PIV) and a tracer particle visualization technique. The pump featured a cylindrical rotor (14.9 mm diameter) within a cylindrical bore, having a radial clearance of 500 µm and operated at rotational speeds varying from 1000 to 12 000 rpm. Corresponding Taylor numbers were 700-101 800, respectively. The critical Taylor number was observed to be highly dependent on the ratio of axial to circumferential velocity, increasing from 1200 to 18 000 corresponding to Rossby numbers from 0 to 0.175. This demonstrated a dramatic stabilizing effect of the axial flow. The size of Taylor vortices was also found to be inversely related to Rossby number. It is concluded that Taylor vortices can enhance the mixing in the annular gap and decrease the dwell time of blood cells in the high-shear-rate region, which has the potential to decrease hemolysis and platelet activation within the blood pump.

Characterizing Pressure and Flow Rate for Aqueous Immersion Surgery.

Hemorrhage control during surgery remains a major clinical challenge for surgeons. Bleeding can affect the safety and efficacy of any surgical procedure. There are well-established methods to address this side-effect of surgery, but all current technologies require the surgeon to direct attention to hemostasis rather than the continuance of the procedure. We have developed a novel surgical method, titled aqueous immersion surgery (AIS), that is able to sustain a bloodless surgical field by providing a controlled hydraulic pressure (immersion pressure) on the bleeding site. Together with the replenishment of an immersion fluid (immersion flow rate), AIS maintains optical clarity of the surgical field. This numerical study was undertaken to investigate the influence of the rate exchange of the immersion fluid on the concentration of blood, hence optical clarity therein. A 3-dimensional multicomponent simulation was performed to evaluate the mixing of blood from an idealized arterial bleeding vessel under pulsatile conditions. With an increase in immersion pressure, bleeding was reduced and increased perfusion was observed. Additionally, the magnitude and direction of the flow field affected the deflection of the bleeding trajectory and, in turn, affected the removal rate of blood from the surgical field. For an idealized case, an optimal immersion flow rate was found for immersion pressures of 100 and 110 mm Hg. From this study, fluid dynamic guidelines are postulated to support future development of AIS.

Investigating the Heart Pump Implant Decision Process: Opportunities for Decision Support Tools to Help.

Clinical decision support tools (DSTs) are computational systems that aid healthcare decision-making. While effective in labs, almost all these systems failed when they moved into clinical practice. Healthcare researchers speculated it is most likely due to a lack of user-centered HCI considerations in the design of these systems. This paper describes a field study investigating how clinicians make a heart pump implant decision with a focus on how to best integrate an intelligent DST into their work process. Our findings reveal a lack of perceived need for and trust of machine intelligence, as well as many barriers to computer use at the point of clinical decision-making. These findings suggest an alternative perspective to the traditional use models, in which clinicians engage with DSTs at the point of making a decision. We identify situations across patients' healthcare trajectories when decision supports would help, and we discuss new forms it might take in these situations.

Study of blood flow in several benchmark micro-channels using a two-fluid approach.

It is known that in a vessel whose characteristic dimension (e.g., its diameter) is in the range of 20 to 500 microns, blood behaves as a non-Newtonian fluid, exhibiting complex phenomena, such as shear-thinning, stress relaxation, and also multi-component behaviors, such as the Fahraeus effect, plasma-skimming, etc. For describing these non-Newtonian and multi-component characteristics of blood, using the framework of mixture theory, a two-fluid model is applied, where the plasma is treated as a Newtonian fluid and the red blood cells (RBCs) are treated as shear-thinning fluid. A computational fluid dynamic (CFD) simulation incorporating the constitutive model was implemented using OpenFOAM® in which benchmark problems including a sudden expansion and various driven slots and crevices were studied numerically. The numerical results exhibited good agreement with the experimental observations with respect to both the velocity field and the volume fraction distribution of RBCs.

Analysis of pressure head-flow loops of pulsatile rotodynamic blood pumps.

The clinical importance of pulsatility is a recurring topic of debate in mechanical circulatory support. Lack of pulsatility has been identified as a possible factor responsible for adverse events and has also demonstrated a role in myocardial perfusion and cardiac recovery. A commonly used method for restoring pulsatility with rotodynamic blood pumps (RBPs) is to modulate the speed profile, synchronized to the cardiac cycle. This introduces additional parameters that influence the (un)loading of the heart, including the timing (phase shift) between the native cardiac cycle and the pump pulses, and the amplitude of speed modulation. In this study, the impact of these parameters upon the heart-RBP interaction was examined in terms of the pressure head-flow (HQ) diagram. The measurements were conducted using a rotodynamic Deltastream DP2 pump in a validated hybrid mock circulation with baroreflex function. The pump was operated with a sinusoidal speed profile, synchronized to the native cardiac cycle. The simulated ventriculo-aortic cannulation showed that the level of (un)loading and the shape of the HQ loops strongly depend on the phase shift. The HQ loops displayed characteristic shapes depending on the phase shift. Increased contribution of native contraction (increased ventricular stroke work [WS ]) resulted in a broadening of the loops. It was found that the previously described linear relationship between WS and the area of the HQ loop for constant pump speeds becomes a family of linear relationships, whose slope depends on the phase shift.

A numerical study of blood flow using mixture theory.

In this paper, we consider the two dimensional flow of blood in a rectangular microfluidic channel. We use Mixture Theory to treat this problem as a two-component system: One component is the red blood cells (RBCs) modeled as a generalized Reiner-Rivlin type fluid, which considers the effects of volume fraction (hematocrit) and influence of shear rate upon viscosity. The other component, plasma, is assumed to behave as a linear viscous fluid. A CFD solver based on OpenFOAM® was developed and employed to simulate a specific problem, namely blood flow in a two dimensional micro-channel, is studied. Finally to better understand this two-component flow system and the effects of the different parameters, the equations are made dimensionless and a parametric study is performed.

Improving the Prediction of 1-Year Right Ventricular Failure After Left Ventricular Assist Device Implantation.

Previous predictive models for postimplant right heart failure (RHF) following left ventricular assist device (LVAD) implantation have demonstrated limited performance on validation datasets and are susceptible to overfitting. Thus, the objective of this study was to develop an improved predictive model with reduced overfitting and improved accuracy in predicting RHF in LVAD recipients. The study involved 11,967 patients who underwent continuous-flow LVAD implantation between 2008 and 2016, with an RHF incidence of 9% at 1 year. Using an eXtreme Gradient Boosting (XGBoost) algorithm, the training data were used to predict RHF at 1 year postimplantation, resulting in promising area under the curve (AUC)-receiver operating characteristic (ROC) of 0.8 and AUC-precision recall curve (PRC) of 0.24. The calibration plot showed that the predicted risk closely corresponded with the actual observed risk. However, the model based on data collected 48 hours before LVAD implantation exhibited high sensitivity but low precision, making it an excellent screening tool but not a diagnostic tool.

Shear Histories Alter Local Shear Effects on Thrombus Nucleation and Growth.

Our goal was to determine the impact of physiological and pathological shear histories on platelet nucleation and thrombus growth at various local shear rates. We designed and characterized a microfluidic device capable of subjecting platelets to shear histories reaching as high as 6700 s - 1 in a single passage. Time-lapse videos of platelets and thrombi are captured using fluorescence microscopy. Thrombi are tracked, and the degree of thrombosis is evaluated through surface coverage, platelet nucleation maps, and ensemble-averaged aggregate areas and intensities. Surface coverage rates were the lowest when platelets deposited at high shear rates following a pathological shear history and were highest at low shear rates following a pathological shear history. Early aggregate area growth rates were significantly larger for thrombi developing at high shear following physiological shear history than at high shear following a pathological shear history. Aggregate vertical growth was restricted when depositing at low shear following a pathological shear history. In contrast, thrombi grew faster vertically following physiological shear histories. These results show that physiological shear histories pose thrombotic risks via volumetric growth, and pathological shear histories drastically promote nucleation. These findings may inform region-based geometries for biomedical devices and refine thrombosis simulations.

A homogenized two-phase computational framework for meso- and macroscale blood flow simulations.

BACKGROUND AND OBJECTIVE: Owing to the complexity of physics linked with blood flow and its associated phenomena, appropriate modeling of the multi-constituent rheology of blood is of primary importance. To this effect, various kinds of computational fluid dynamic models have been developed, each with merits and limitations. However, when additional physics like thrombosis and embolization is included within the framework of these models, computationally efficient scalable translation becomes very difficult. Therefore, this paper presents a homogenized two-phase blood flow framework with similar characteristics to a single fluid model but retains the flow resolution of a classical two-fluid model. The presented framework is validated against four different sets of experiments. METHODS: The two-phase model of blood presented here is based on the classical diffusion-flux framework. Diffusion flux models are known to be less computationally expensive than two-fluid multiphase models since the numerical implementation resembles single-phase flow models. Diffusion flux models typically use empirical slip velocity correlations to resolve the motion between phases. However, such correlations do not exist for blood. Therefore, a modified slip velocity equation is proposed, derived rigorously from the two-fluid governing equations. An additional drag law for red blood cells (RBCs) as a function of volume fraction is evaluated using a previously published cell-resolved solver. A new hematocrit-dependent expression for lift force on RBCs is proposed. The final governing equations are discretized and solved using the open-source software OpenFOAM. RESULTS: The framework is validated against four sets of experiments: (i) flow through a rectangular microchannel to validate RBC velocity profiles against experimental measurements and compare computed hematocrit distributions against previously reported simulation results (ii) flow through a sudden expansion microchannel for comparing experimentally obtained contours of hematocrit distributions and normalized cell-free region length obtained at different flowrates and inlet hematocrits, (iii) flow through two hyperbolic channels to evaluate model predictions of cell-free layer thickness, and (iv) flow through a microchannel that mimics crevices of a left ventricular assist device to predict hematocrit distributions observed experimentally. The simulation results exhibit good agreement with the results of all four experiments. CONCLUSION: The computational framework presented in this paper has the advantage of resolving the multiscale physics of blood flow while still leveraging numerical techniques used for solving single-phase flows. Therefore, it becomes an excellent candidate for addressing more complicated problems related to blood flow, such as modeling mechanical entrapment of RBCs within blood clots, predicting thrombus composition, and visualizing clot embolization.

Effect of Artificial Lung Fiber Bundle Geometric Design on Micro- and Macro-scale Clot Formation.

The hollow fiber membrane bundle is the functional component of artificial lungs, transferring oxygen and carbon dioxide to and from the blood. It is also the primary location of blood clot formation and propagation in these devices. The geometric design of fiber bundles is defined by a narrow range of parameters that determine gas exchange efficiency and blood flow resistance, such as fiber packing density, path length, and frontal area. However, these parameters also affect thrombosis. This study investigated the effect of these parameters on clot formation using 3-D printed flow chambers that mimic the geometry and blood flow patterns of fiber bundles. Hollow fibers were represented by an array of vertical micro-rods (380 micron diameter) arranged with varying packing densities (40, 50, and 60%) and path lengths (2 and 4 cm). Blood was pumped through the device corresponding to three mean blood flow velocities (16, 20, and 25 cm/min). Results showed that (1) clot formation decreases dramatically with decreasing packing density and increasing blood flow velocity, (2) clot formation at the outlet of fiber bundle enhances deposition upstream, and consequently (3) greater path length provides more clot-free fiber surface area for gas exchange than a shorter path length. These results can be used to create less thrombogenic, more efficient artificial lung designs. Translational Impact Sentence: Fiber bundle parameters, such as decreased packing density, increased blood flow velocity, and a longer path length, can be used to design a less thrombogenic, more efficient artificial lung to extend functionality.

Limitations of receiver operating characteristic curve on imbalanced data: Assist device mortality risk scores.

OBJECTIVE: In the left ventricular assist device domain, the receiver operating characteristic is a commonly applied metric of performance of classifiers. However, the receiver operating characteristic can provide a distorted view of classifiers' ability to predict short-term mortality due to the overwhelmingly greater proportion of patients who survive, that is, imbalanced data. This study illustrates the ambiguity of the receiver operating characteristic in evaluating 2 classifiers of 90-day left ventricular assist device mortality and introduces the precision recall curve as a supplemental metric that is more representative of left ventricular assist device classifiers in predicting the minority class. METHODS: This study compared the receiver operating characteristic and precision recall curve for 2 classifiers for 90-day left ventricular assist device mortality, HeartMate Risk Score and Random Forest for 800 patients (test group) recorded in the Interagency Registry for Mechanically Assisted Circulatory Support who received a continuous-flow left ventricular assist device between 2006 and 2016 (mean age, 59 years; 146 female vs 654 male patients), in whom 90-day mortality rate is only 8%. RESULTS: The receiver operating characteristic indicates similar performance of Random Forest and HeartMate Risk Score classifiers with respect to area under the curve of 0.77 and Random Forest 0.63, respectively. This is in contrast to their precision recall curve with area under the curve of 0.43 versus 0.16 for Random Forest and HeartMate Risk Score, respectively. The precision recall curve for HeartMate Risk Score showed the precision rapidly decreased to only 10% with slightly increasing sensitivity. CONCLUSIONS: The receiver operating characteristic can portray an overly optimistic performance of a classifier or risk score when applied to imbalanced data. The precision recall curve provides better insight about the performance of a classifier by focusing on the minority class.