Systems biology of hemostasis
The formation of a blood clot is a complex process that involves the adhesion, aggregation, and activation of blood cells called platelets and the enzymatic network of coagulation that ultimately results in the formation of the biopolymer fibrin. All of this occurs in a highly dynamic biophysical environment regulated by blood flow. In this project, we combine mathematical and microfluidic models of blood clot formation to reveal new mechanisms that regulate bleeding and thrombotic disorders. The figure above describes the overall process of how computational models can lead to new discoveries in coagulation dynamics. Here, in the case of hemophilia A, the mathematical model made the unexpected prediction that another protein, factor V, was a strong modifier of thrombin generation. A prediction that was confirmed in thrombin generation assays and microfluidic models of hemostasis. Current work is focused on using a similar approach to understand organ specific bleeding patterns in the context of genetic and acquired coagulopathies.
This project is in collaboration with Karin Leiderman (Colorado School of Mines), Aaron Fogelson (University of Utah), Suzanne Sindi (UC-Merced), and Mac Monroe (UNC-Chapel Hill). This project is funded by NIH award R01HL1984.
Related Publications
K. Leiderman, S.S. Sindi, D.M. Monroe, A.L. Fogelson, K.B. Neeves. The art and science of building a computational model to understand hemostasis. Seminar on Thrombosis and Hemostasis, 47 (2021):129-138. DOI: 10.1055/s-0041-1722861.
K.G. Link, M.T. Stobb, D.M. Monroe, A.L. Fogelson, S.S. Sindi, K.B. Neeves, K. Leiderman. Computationally driven discovery in coagulation. Arteriosclerosis, Thrombosis, and Vascular Biology, 41 (2021):79-86. 1. DOI: 10.1161/ATVBAHA.120.314648.
K.G. Link, M.T. Stobb, M.G. Sorrells, M. Bortot, K. Ruegg, M.J. Manco-Johnson, J.A. Di Paola, S.S. Sindi, A.L. Fogelson, K. Leiderman, K.B. Neeves. A mathematical model of coagulation under flow identifies factor V as a modifier of thrombin generation in hemophilia A. Journal of Thrombosis and Haemostasis, 18 (2020): 306-317. DOI: 10.1111/jth.14653
K.G. Link, M.G. Sorrells, N. Danes, K.B. Neeves, K. Leiderman, A.L. Fogelson. A mathematical model of platelet aggregation in an extravascular injury under flow. Multiscale Modeling and Simulation,18 (2020):1489-1524. DOI: 10.1137/20M1317785.
K.G. Link, M.T. Stobb, J. Di Paola, K.B. Neeves, A.L. Fogelson, S.S. Sindi, K. Leiderman. A local and global sensitivity analysis of a mathematical model of coagulation and platelet deposition under flow. PLoS One, 13 (2018): e0200917. DOI: 10.1371/journal.pone.0200917
A.A. Onasoga-Jarvis, K. Leiderman, A.L. Fogelson, M. Wang, M.J. Manco-Johnson, J.A. Di Paola, K.B. Neeves. The effect of factor VIII deficiencies and replacement and bypass therapies on thrombus formation under venous flow conditions in microfluidic and computational models. PLoS One, 8 (2013): e78732. DOI: 10.1371/journal.pone.0054680