title: A systems approach to hemostasis: 3. Thrombus consolidation regulates intrathrombus solute transport and local thrombin activity.
abstract: Hemostatic thrombi formed after a penetrating injury have a distinctive structure in which a core of highly activated, closely packed platelets is covered by a shell of less-activated, loosely packed platelets. We have shown that differences in intrathrombus molecular transport emerge in parallel with regional differences in platelet packing density and predicted that these differences affect thrombus growth and stability. Here we test that prediction in a mouse vascular injury model. The studies use a novel method for measuring thrombus contraction in vivo and a previously characterized mouse line with a defect in integrin αIIbβ3 outside-in signaling that affects clot retraction ex vivo. The results show that the mutant mice have a defect in thrombus consolidation following vascular injury, resulting in an increase in intrathrombus transport rates and, as predicted by computational modeling, a decrease in thrombin activity and platelet activation in the thrombus core. Collectively, these data (1) demonstrate that in addition to the activation state of individual platelets, the physical properties of the accumulated mass of adherent platelets is critical in determining intrathrombus agonist distribution and platelet activation and (2) define a novel role for integrin signaling in the regulation of intrathrombus transport rates and localization of thrombin activity.
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 Medicine and.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Tomaiuolo
authors.affiliation: Department of Medicine and.
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Medicine and.
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Colace
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 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; D006801:Humans; D051379:Mice; D008955:Models, Cardiovascular; D015539:Platelet Activation; D021381:Protein Transport; D013917:Thrombin / Q000378:metabolism*
chemical_list: D013917:Thrombin