Normal haemostasis is an important physiological mechanism that prevents excessive bleeding during trauma, whereas the pathological thrombosis especially in diabetics leads to increased incidence of heart attacks and strokes as well as peripheral vascular events. In this work, we propose a new multiscale framework that integrates seamlessly four key components of blood clotting, namely transport of coagulation factors, coagulation kinetics, blood cell mechanics and platelet adhesive dynamics, to model the development of thrombi under physiological and pathological conditions. We implement this framework to simulate platelet adhesion due to the exposure of tissue factor in a three-dimensional microchannel. Our results show that our model can simulate thrombin-mediated platelet activation in the flowing blood, resulting in platelet adhesion to the injury site of the channel wall. Furthermore, we simulate platelet adhesion in diabetic blood, and our results show that both the pathological alterations in the biomechanics of blood cells and changes in the amount of coagulation factors contribute to the excessive platelet adhesion and aggregation in diabetic blood. Taken together, this new framework can be used to probe synergistic mechanisms of thrombus formation under physiological and pathological conditions, and open new directions in modelling complex biological problems that involve several multiscale processes.

Mechanical interactions between flowing and coagulated blood (thrombus) are crucial in dictating the deformation and remodeling of a thrombus after its formation in hemostasis. We propose a fully-Eulerian, three-dimensional, phase-field model of thrombus that is calibrated with existing in vitro experimental data. This phase-field model considers spatial variations in permeability and material properties within a single unified mathematical framework derived from an energy perspective, thereby allowing us to study effects of thrombus microstructure and properties on its deformation and possible release of emboli under different hemodynamic conditions. Moreover, we combine this proposed thrombus model with a particle-based model which simulates the initiation of the thrombus. The volume fraction of a thrombus obtained from the particle simulation is mapped to an input variable in the proposed phase-field thrombus model. The present work is thus the first computational study to integrate the initiation of a thrombus through platelet aggregation with its subsequent viscoelastic responses to various shear flows. This framework can be informed by clinical data and potentially be used to predict the risk of diverse thromboembolic events under physiological and pathological conditions. Thromboembolism is associated with detachment of small thrombus pieces from the bulk in the blood vessel. These detached pieces, also known as emboli, travel through the blood flow and may block other vessels downstream, e.g., they may plug the deep veins of the leg, groin or arm, leading to venous thromboembolism (VTE). VTE is a significant cause of morbidity and mortality and it affects more than 900,000 people in the United States and result in approximately 100,000 deaths every year. Mechanical interaction between flowing blood and a thrombus is crucial in determining the deformation of the thrombus and the possibility of releasing emboli. In this study, we develop a phase-field model that is capable of describing the structural properties of a thrombus and its biomechanical properties under different blood flow conditions. Moreover, we combine this thrombus model with a particle-based model which simulates the initiation of the thrombus. This combined framework is the first computational study to simulate the development of a thrombus from platelet aggregation to its subsequent viscoelastic responses to various shear flows. Informed by clinical data, this framework can be used to predict the risk of diverse thromboembolic events under physiological and pathological conditions.

The spleen, the largest secondary lymphoid organ in humans, not only fulfils a broad range of immune functions, but also plays an important role in red blood cell’s (RBC) life cycle. Although much progress has been made to elucidate the critical biological processes involved in the maturation of young RBCs (reticulocytes) as well as removal of senescent RBCs in the spleen, the underlying mechanisms driving these processes are still obscure. Herein, we perform a computational study to simulate the passage of RBCs through interendothelial slits (IES) in the spleen at different stages of their lifespan and investigate the role of the spleen in facilitating the maturation of reticulocytes and in clearing the senescent RBCs. Our simulations reveal that at the beginning of the RBC life cycle, intracellular non-deformable particles in reticulocytes can be biomechanically expelled from the cell upon passage through IES, an insightful explanation of why this peculiar “pitting” process is spleen-specific. Our results also show that immature RBCs shed surface area by releasing vesicles after crossing IES and progressively acquire the biconcave shape of mature RBCs. These findings likely explain why RBCs from splenectomized patients are significantly larger than those from nonsplenectomized subjects. Finally, we show that at the end of their life span, senescent RBCs are not only retained by IES due to reduced deformability but also become susceptible to mechanical lysis under shear stress. This finding supports the recent hypothesis that transformation into a hemolyzed ghost is a prerequisite for phagocytosis of senescent RBCs. Altogether, our computational investigation illustrates critical biological processes in the spleen that cannot be observed in vivo or in vitro and offer insights into the role of the spleen in the RBC physiology.

Emerging clinical evidence suggests that thrombosis in the microvasculature of patients with Coronavirus disease 2019 (COVID-19) plays an essential role in dictating the disease progression. Because of the infectious nature of SARS-CoV-2, patients’ fresh blood samples are limited to access for in vitro experimental investigations. Herein, we employ a novel multiscale and multiphysics computational framework to perform predictive modeling of the pathological thrombus formation in the microvasculature using data from patients with COVID-19. This framework seamlessly integrates the key components in the process of blood clotting, including hemodynamics, transport of coagulation factors and coagulation kinetics, blood cell mechanics and adhesive dynamics, and thus allows us to quantify the contributions of many prothrombotic factors reported in the literature, such as stasis, the derangement in blood coagulation factor levels and activities, inflammatory responses of endothelial cells and leukocytes to the microthrombus formation in COVID-19. Our simulation results show that among the coagulation factors considered, antithrombin and factor V play more prominent roles in promoting thrombosis. Our simulations also suggest that recruitment of WBCs to the endothelial cells exacerbates thrombogenesis and contributes to the blockage of the blood flow. Additionally, we show that the recent identification of flowing blood cell clusters could be a result of detachment of WBCs from thrombogenic sites, which may serve as a nidus for new clot formation. These findings point to potential targets that should be further evaluated, and prioritized in the anti-thrombotic treatment of patients with COVID-19. Altogether, our computational framework provides a powerful tool for quantitative understanding of the mechanism of pathological thrombus formation and offers insights into new therapeutic approaches for treating COVID-19 associated thrombosis.

Microaneurysms (MAs) are one of the earliest clinically visible signs of diabetic retinopathy (DR). MA leakage or rupture may precipitate local pathology in the surrounding neural retina that impacts visual function. Thrombosis in MAs may affect their turnover time, an indicator associated with visual and anatomic outcomes in the diabetic eyes. In this work, we perform computational modeling of blood flow in microchannels containing various MAs to investigate the pathologies of MAs in DR. The particle-based model employed in this study can explicitly represent red blood cells (RBCs) and platelets as well as their interaction in the blood flow, a process that is very difficult to observe in vivo. Our simulations illustrate that while the main blood flow from the parent vessels can perfuse the entire lumen of MAs with small body-to-neck ratio (BNR), it can only perfuse part of the lumen in MAs with large BNR, particularly at a low hematocrit level, leading to possible hypoxic conditions inside MAs. We also quantify the impacts of the size of MAs, blood flow velocity, hematocrit and RBC stiffness and adhesion on the likelihood of platelets entering MAs as well as their residence time inside, two factors that are thought to be associated with thrombus formation in MAs. Our results show that enlarged MA size, increased blood velocity and hematocrit in the parent vessel of MAs as well as the RBC-RBC adhesion promote the migration of platelets into MAs and also prolong their residence time, thereby increasing the propensity of thrombosis within MAs. Overall, our work suggests that computational simulations using particle-based models can help to understand the microvascular pathology pertaining to MAs in DR and provide insights to stimulate and steer new experimental and computational studies in this area.