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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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)