To prevent the loss of blood following a break in blood vessels, components in blood and vessel wall interact rapidly to form a blood clot (thrombus) to limit hemorrhage. This hemostatic response is rapid and regulated, since excessive and inappropriate clotting reduces the patency of blood flow. While knockout mice provide qualitative results about the role of particular hemostatic components, the mathematical and computational models can suggest threshold values of particular elements critical for hemostasis. Determining such thresholds will help identify hemostatic risk factors in human population. This has significant biomedical implications. For instance, deep vein thrombosis affects 250,000 Americans each year and leads to 20,000 deaths mainly from clot fragments that break off from the thrombus and cause pulmonary embolisms. The incidence will increase as the population ages. Developing accurate, quantitative models of thrombus formation that help us understand the physical and biochemical processes involved in clot structure and stability will contribute to the development of new diagnostic approaches and therapeutic strategies.
The overall goal of this proposal is to develop three-dimensional multiscale mathematical models and a computational toolkit for simulating thrombus formation. These models will be validated with specifically designed experiments to test predictions of thrombus development, structure and stability. Moreover, the development of reasonable models will serve as a generator of new hypotheses that can be tested in experiments in vivo. To achieve this goal, a new collaboration has been formed between Dr. Alber and Dr. Xu (Notre Dame), Dr. Rosen (Indiana University Medical School) and Dr. Jiang (Los Alamos National Lab). To bring different scale levels of thrombus model together, new mathematical techniques and computational schemes will be developed and these will include elements of stochastic analysis, nonlinear analysis and kinetic theory. New methods will include coarsening methods, new numerical schemes, error estimates of numerical solutions as well as parallelization algorithms for the coupled discrete and continuous models needed for the long time simulations. The mathematical and computational models will incorporate many biological processes (platelet interactions, coagulation pathways, hemodynamic effects) into the simulation thus integrating biological fields that have traditionally been studied separately.
Normal 0 false false false EN-US X-NONE X-NONE Thrombosis is one of major causes of morbidity and mortality in the developed world. As the population ages and diabetes becomes more prevalent, the rates of thrombosis also increase. Blood clots are formed in coronary arteries, causing heart attacks, and in brain vessels, causing ischemic strokes. Venous thromboembolic disease alone is a significant biomedical problem causing 900,000 hospitalizations per year in the US resulting in 300,000 deaths. This collaborative project resulted in development of novel multiscale 3-dimensional mathematical models and a computational toolkit for simulating different stages of the thrombus formation. The model was validated using specifically designed experiments in mice and microfluidic devices to test predictions of early thrombus development, its structure and stability. In particular, model predictions of different roles that platelets and fibrin network play in regulating clot growth can yield new approaches for preventing bleeding, thrombosis, and embolization, and subsequently suggesting new patient specific treatment strategies. Better understanding of the mechanisms of clot growth and its limitations under blood flow provided by running simulations using new computational toolkit will help physicians to estimate risk of thrombotic disease for an individual patient by identifying critical values of parameters of processes regulating thrombogenesis The project resulted in interdisciplinary training of three graduate students and three postdoctoral associates in multiscale modeling approaches, computational implementation of models on High-Performance Computing Clusters and analysis of experimental images of blood clots. Two international workshops with strong educational components were organized by the investigators. Investigators in collaboration with teachers from Michigan and Indiana developed an interactive web site with electronic tutorial with separate sections aimed at undergraduate and high school students to provide educational materials on stochastic approaches in mathematical and computational biology. .
