Computational Approaches to Studying Thrombus Development

Abstract

Abstract-In addition to descriptive biological models, many computational models have been developed for hemostasis/ thrombosis that provide quantitative characterization of thrombus development. Simulations using computational models that have been developed for coagulation reactions, platelet activation, and fibrinogen assembly have been shown to be in close agreement with experimental data. Models of processes involved in hemostasis/thrombosis are being integrated to simulate the development of the thrombus simultaneously in time and space. Key Words: blood coagulation Ⅲ blood flow Ⅲ coagulation Ⅲ platelets Ⅲ thrombosis Ⅲ computational model Ⅲ stochastic multiscale model Ⅲ thrombus development S ignificant progress has been made in our understanding of the hemostatic response. For instance, coagulation pathways 1 have been developed that describe the interactions among different elements and provide insight into the regulation of the response. Similarly, advances in platelet biology 2 have elucidated pathways of platelet activation and identified and characterized molecular components involved in intracellular signaling, as well as surface proteins mediating adhesion to the damaged vessel wall, to other platelets, and to other thrombus components. Furthermore, the development of transgenic, 3,4 gene knockout, and gene knock-in technologies has enabled exploration of the physiological roles of individual components in vivo using sophisticated hemostatic experimental systems. More recently, genomic and proteomic approaches have identified new elements modifying the hemostatic response.The initial identification of hemostatic components and description of coagulation or platelet signaling pathways were qualitative, 4,5 describing the order of interaction among components in coagulation or platelet behavior. These biological and biochemical models were extremely valuable, suggesting how these processes might be regulated and providing an understanding of how deficiencies or dysregulation of particular components leads to pathological states.In addition to these descriptive biological models, computational models have been developed for hemostatic processes that provide quantitative characterization of thrombus development. For instance, the tissue factor (TF)-initiated coagulation model introduced by Hockin et al 6 presented a quantitative description of the network of coagulation reactions. The model correctly predicted that there was a TF concentration threshold required to activate the coagulation system to generate the thrombin required for a hemostatic response. In addition, the computational model introduced by Purvis et al 7 to simulate ADP-mediated platelet activation provided insight into possible mechanisms of negativefeedback signaling and cell-to-cell variation across platelet populations. Furthermore, the kinetic model of fibrin polymerization introduced by Weisel and Nagaswami 8 revealed that changes in the rate of fibrinopeptide cleavage were sufficient to explain many nonintuitive experimental obs...

A haemodynamic predictor of intraluminal thrombus formation in abdominal aortic aneurysms

“…That is, in contrast to prior haemodynamic studies (see reviews [4][5][6]) of thrombus formation in regions of arterial injury (e.g. eroded stenoses or ruptured atherosclerotic plaques) or within medical implants (e.g.…”

“…The latter is yet important and necessitates multiscale, multiphysics approaches as being pursued by others (cf. [4][5][6]). Nevertheless, a phenomenological metric could also be very important, particularly in treatment planning.…”

“…The first phase actually involves three steps as well: the activation, adhesion and aggregation of platelets. Many prior studies have focused on specific aspects of the mechanisms underlying thrombus formation within a general haemodynamic field as revealed by multiple papers [4][5][6]. In particular, there has been an appropriate move towards multiscale models wherein one can capture contributions ranging from molecular-level chemical reaction kinetics to macroscopic haemodynamics.…”

A continuum model for platelet plug formation, growth and deformation

“…In recent years, a number of numerical models for studying primary haemostasis, secondary haemostasis and clot stabilization and retraction has been proposed [Xu et al, 2011], , [Moiseyev and BarYoseph, 2013]. It is possible to classify these models in three major categories: platelet plug formation models, blood clot formation and/or retraction models and blood clot phase change over time models.…”

“…This already brings to a deeper understanding of the haemostatic process itself [Xu et al, 2012]. It is also necessary to verify models through experiments, given the large number of parameters involved [Xu et al, 2011]. Once a model is verified, it could be used for instance to predict the best design associated to cardiovascular devices [Moiseyev and Bar-Yoseph, 2013].…”