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WIREs Syst Biol Med
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Multiscale models of thrombogenesis

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Abstract To restrict the loss of blood follow from the rupture of blood vessels, the human body rapidly forms a clot consisting of platelets and fibrin. However, to prevent pathological clotting within vessels as a result of vessel damage, the response must be regulated. Clots forming within vessels (thrombi) can restrict the flow of blood causing damage to tissues in the flow field. Additionally, fragments dissociating from the primary thrombus (emboli) may lodge and clog vessels in the brain (causing ischemic stroke) or lungs (resulting in pulmonary embolism). Pathologies related to the obstruction of blood flow through the vasculature are the major cause of mortality in the United States. Venous thromboembolic disease alone accounts for 900,000 hospitalizations and 300,000 deaths per year and the incidence will increase as the population ages (Wakefield et al. J Vasc Surg 2009, 49:1620–1623). Thus, understanding the interplay between the many processes involved in thrombus development is of significant biomedical value. In this article, we first review computational models of important subprocesses of hemostasis/thrombosis including coagulation reactions, platelet activation, and fibrin assembly, respectively. We then describe several multiscale models integrating these subprocesses to simulate temporal and spatial development of thrombi. The development of validated computational models and predictive simulations will enable one to explore how the variation of multiple hemostatic factors affects thrombotic risk providing an important new tool for thrombosis research. WIREs Syst Biol Med 2012 doi: 10.1002/wsbm.1160 This article is categorized under: Models of Systems Properties and Processes > Cellular Models Developmental Biology > Developmental Processes in Health and Disease Physiology > Mammalian Physiology in Health and Disease Biological Mechanisms > Regulatory Biology

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Force‐strain curve for single fibrin fiber obtain by Hudson et al.33: (a)–(d) shows a single‐suspended fiber stretched to breaking (d) by an atomic force microscopy (AFM) tip. (Plot) The black points depict single fibrin fiber force‐strain data determined by calibrated lateral AFM force measurement. The line depicts the worm‐ like‐chain (WLC) fit using two fitting parameters: the persistence and contour lengths. (Reprinted with permission from Ref 33. Copyright 2010 Elsevier)

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Thrombus growth in wild‐type (WT) and low factor VII (FVII) mice53 (a) The volumes of developing thrombi in wt and low FII mice were calculated using the image processing algorithms on z‐stacks of consecutive structure. The time interval between structures is 80 seconds. (b) The multiscale two‐dimensional (2D) simulation of thrombogenesis was used to determine thrombin levels in thrombi developing with different FVII levels. Open circles (FVII) 100%; line, 0.1% of wt. (Reprinted with permission from Ref 53. Copyright 2010 Elsevier)

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Force‐extension curve of a cylindrical fibrin clot obtained by Brown et al.26 As the strain increases, the force on the clot increases linearly until a strain of ∼1.2 is reached, at which point the sample hardens and enters a new regime with a steeper slope (black solid line). The force‐extension curve (black solid line) is fit using a constitutive model that takes clot microstructure and protein unfolding into account (red line). Without molecular unfolding (like collagen), the model (black dashed line) rapidly diverges from the experimental data (black solid). (Reprinted with permission from Ref 26. Copyright 2009 American Association for the Advancement of Science)

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