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.

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.

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.

Exploratory Simulation of Thrombosis in a Temporary LVAD Catheter Pump within a Virtual In-vivo Left Heart Environment.

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.

Trans-aortic Valvular Ejection Fraction for Monitoring Recovery of Patients with Ventricular Systolic Heart Failure.

Durable mechanical circulatory support in the form of left ventricular (LV) assist device (LVAD) therapy is increasingly considered in the context of the recovery of native cardiac function. Progressive improvement in LV function may facilitate LVAD explantation and a resultant reduction in device-related risk. However, ascertaining LV recovery remains a challenge. In this study, we investigated the use of trans-aortic valvular flow rate and trans-LVAD flow rate to assess native LV systolic function using a well-established lumped parameter model of the mechanically assisted LV with pre-existing systolic dysfunction. Trans-aortic valvular ejection fraction (TAVEF) was specifically found to characterize the preload-independent contractility of the LV. It demonstrated excellent sensitivity to simulated pharmacodynamic stress tests and volume infusion tests. TAVEF may prove to be useful in the ascertainment of LV recovery in LVAD-supported LVs with pre-existing LV systolic dysfunction.

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.

In search of similarity in adverse events journeys of patients with left ventricular assist devices.

OBJECTIVE: The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) Event data set contains an expansive collection of longitudinal evidence of the course of adverse events (AEs) of >15,000 patients who have received a left ventricular assist device (LVAD). Buried in the huge Event data set is knowledge that can provide a deeper understanding of the patterns of the "AE journey" of patients with LVAD. Thus, the goal of this study was to examine the Event data set from a comprehensive perspective to identify unique relationships and patterns of AEs, alert potential challenges, and suggest future research directions. METHODS: A sequential pattern mining algorithm called SPADE (ie, Sequential PAttern Discovery using Equivalence classes) was applied to 86,912 recorded AEs of 15,820 patients with a continuous-flow LVAD between 2008 and 2016, extracted from the publicly accessible INTERMACS registry. The patterns of AE journey were investigated by posing 5 descriptive research questions about most common types of AE, concomitant AEs, AE sequences, AE subsequences, and interesting relations between AEs. RESULTS: The analysis revealed several characteristics of patterns of the AE journey of patients who received an LVAD that accounts for the types and temporal ordering of successive AEs, combinations of AEs, and their timing after surgery. CONCLUSIONS: The high diversity and sparsity of the types and timing of AE occurrences make the AE journeys of patients dissimilar from each other, impeding the discovery of highly-patterned AE journeys among the patients. This study suggests 2 salient directions for future studies to tackle this issue using cluster analysis to cluster patients into more similar groups and translate these results into a practical clinical tool to forecast the next AE based on the history of previous AEs.

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.

Extracting Mural and Volumetric Growth Patterns of Platelet Aggregates on Engineered Surfaces by Use of an Entity Tracking Algorithm.

Thrombosis is a major complication that can occur in both blood-contacting devices and regions and in regions of vascular damage. Microfluidic devices are popular templates to model various thrombogenic settings and to assess conditions that lead to bulk channel occlusion. However, area-averaged measurements miss the opportunity to extract real-time information on thrombus evolution and early dynamics of thrombus formation and propagation, which result in late-stage bulk channel occlusion. To clarify these dynamics, we have developed a standalone tracking algorithm that uses consecutive image connectivity and minimal centroid distance mappings to uniquely index all appearing thrombi in fluorescence time-lapse videos http://links.lww.com/ASAIO/A887 , and http://links.lww.com/ASAIO/A888 . This leads to measurements of all individual aggregates that can in turn be studied as ensembles. We applied tracking to fluorescence time-lapse videos http://links.lww.com/ASAIO/A887 , and http://links.lww.com/ASAIO/A888 of thrombosis across both collagen-functionalized substrate and across the surface of a roughened titanium alloy (Ti6Al4V) at a shear rate of 4000 s -1 . When comparing ensemble-averaged measurements to area-averaged metrics, we unveil immediate, steady thrombus growth at early phases on collagen surfaces and unstable thrombus attachment to roughened Ti6Al4V surfaces on Ti6Al4V surfaces. Additionally, we introduce tracked thrombus eccentricity and fluorescence intensity as additional volumetric measures of thrombus growth that relate back to the primary thrombosis mechanism at play. This work advocates for the complementation of surface macrostate metrics with characteristic thrombus microstate growth patterns to accurately predict critical thrombosis events.

Biological Response to Sintered Titanium in Left Ventricular Assist Devices: Pseudoneointima, Neointima, and Pannus.

Titanium alloys have traditionally been used in blood-contacting cardiovascular devices, including left ventricular assist devices (LVADs). However, titanium surfaces are susceptible to adverse coagulation, leading to thrombogenesis and stroke. To improve hemocompatibility, LVAD manufacturers introduced powder sintering on blood-wetted surfaces in the 1980s to induce endothelialization. This technique has been employed in multiple contemporary LVADs on the pump housing, as well as the interior and exterior of the inflow cannula. Despite the wide adoption of sintered titanium, reported biologic response over the past several decades has been highly variable and apparently unpredictable-including combinations of neointima, pseudoneoimtima, thrombus, and pannus. We present a history of sintered titanium used in LVAD, a review of accumulated clinical outcomes, and a synopsis of gross appearance and composition of various depositions found clinically and in animal studies, which is unfortunately confounded by the variability and inconsistency in terminology. Therefore, this review endeavors to introduce a unified taxonomy to harmonize published observations of biologic response to sintered titanium in LVADs. From these data, we are able to deduce the natural history of the biologic response to sintered titanium, toward development of a deterministic model of the genesis of a hemocompatible neointima.

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.

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.

Uncertainty quantification of a thrombosis model considering the clotting assay PFA-100®.

Mathematical models of thrombosis are currently used to study clinical scenarios of pathological thrombus formation. As these models become more complex to predict thrombus formation dynamics high computational cost must be alleviated and inherent uncertainties must be assessed. Evaluating model uncertainties allows 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 facilitated thanks to time-evolving polynomial chaos expansions used as a parametric surrogate for the full thrombosis model considering two quantities of interest; namely, thrombus volume and occlusion percentage. The surrogate is thoroughly validated and provides a straightforward access to a global sensitivity analysis via computation of Sobol' coefficients. Six out of 15 parameters linked to thrombus consitution, vWF activity, and platelet adhesion dynamics were found to be most influential in the simulation variability considering only individual effects; while parameter interactions are highlighted when considering the total Sobol' indices. The influential parameters are related to thrombus constitution, vWF activity, and platelet to platelet adhesion dynamics. The surrogate model allowed to predict realistic PFA-100® closure times of 300,000 virtual cases that followed the trends observed in clinical data. The current methodology could be used including common anti-platelet therapies to identify scenarios that preserve the hematological balance.

Physiology of Continuous-Flow Left Ventricular Assist Device Therapy.

The expanding use of continuous-flow left ventricular assist devices (CF-LVADs) for end-stage heart failure warrants familiarity with the physiologic interaction of the device with the native circulation. Contemporary devices utilize predominantly centrifugal flow and, to a lesser extent, axial flow rotors that vary with respect to their intrinsic flow characteristics. Flow can be manipulated with adjustments to preload and afterload as in the native heart, and ascertainment of the predicted effects is provided by differential pressure-flow (H-Q) curves or loops. Valvular heart disease, especially aortic regurgitation, may significantly affect adequacy of mechanical support. In contrast, atrioventricular and ventriculoventricular timing is of less certain significance. Although beneficial effects of device therapy are typically seen due to enhanced distal perfusion, unloading of the left ventricle and atrium, and amelioration of secondary pulmonary hypertension, negative effects of CF-LVAD therapy on right ventricular filling and function, through right-sided loading and septal interaction, can make optimization challenging. Additionally, a lack of pulsatile energy provided by CF-LVAD therapy has physiologic consequences for end-organ function and may be responsible for a series of adverse effects. Rheological effects of intravascular pumps, especially shear stress exposure, result in platelet activation and hemolysis, which may result in both thrombotic and hemorrhagic consequences. Development of novel solutions for untoward device-circulatory interactions will facilitate hemodynamic support while mitigating adverse events. © 2021 American Physiological Society. Compr Physiol 12:1-37, 2021.

A Continuum Model for the Unfolding of von Willebrand Factor.

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.

Influence of shear rate and surface chemistry on thrombus formation in micro-crevice.

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.

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.