title: A systems approach to hemostasis: 2. Computational analysis of molecular transport in the thrombus microenvironment.
abstract: Hemostatic thrombi formed after a penetrating injury have a heterogeneous architecture in which a core of highly activated, densely packed platelets is covered by a shell of less-activated, loosely packed platelets. In the first manuscript in this series, we show that regional differences in intrathrombus protein transport rates emerge early in the hemostatic response and are preserved as the thrombus develops. Here, we use a theoretical approach to investigate this process and its impact on agonist distribution. The results suggest that hindered diffusion, rather than convection, is the dominant mechanism responsible for molecular movement within the thrombus. The analysis also suggests that the thrombus core, as compared with the shell, provides an environment for retaining soluble agonists such as thrombin, affecting the extent of platelet activation by establishing agonist-specific concentration gradients radiating from the site of injury. This analysis accounts for the observed weaker activation and relative instability of platelets in the shell and predicts that a failure to form a tightly packed thrombus core will limit thrombin accumulation, a prediction tested by analysis of data from mice with a defect in clot retraction.
authors.affiliation: Department of Medicine, and.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Tomaiuolo
authors.affiliation: Department of Medicine, and.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Stalker
authors.affiliation: Department of Medicine, and Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA.
authors.forename: John D
authors.initials: JD
authors.lastname: Welsh
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Diamond
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA.
authors.forename: Talid
authors.initials: T
authors.lastname: Sinno
authors.affiliation: Department of Medicine, and.
authors.forename: Lawrence F
authors.identifier: http://orcid.org/0000-0003-0093-8886
authors.initials: LF
authors.lastname: Brass
mesh_terms: D000818:Animals; D001777:Blood Coagulation; D003198:Computer Simulation; D006801:Humans; D051379:Mice; D008955:Models, Cardiovascular; D015539:Platelet Activation; D021381:Protein Transport; D013917:Thrombin / Q000378:metabolism*
chemical_list: D013917:Thrombin