title: Simulated Thrombin Generation in the Presence of Surface-Bound Heparin and Circulating Tissue Factor.
abstract: An expanded computational model of surface induced thrombin generation was developed that includes hemodynamic effects, 22 biochemical reactions and 44 distinct chemical species. Surface binding of factors V, VIII, IX, and X was included in order to more accurately simulate the formation of the surface complexes tenase and prothrombinase. In order to model these reactions, the non-activated, activated and inactivated forms were all considered. This model was used to investigate the impact of surface bound heparin on thrombin generation with and without the additive effects of thrombomodulin (TM). In total, 104 heparin/TM pairings were evaluated (52 under venous conditions, 52 under arterial conditions), the results demonstrating the synergistic ability of heparin and TM to reduce thrombin generation. Additionally, the role of circulating tissue factor (TF(p)) was investigated and compared to that of surface-bound tissue factor (TF(s)). The numerical results suggest that circulating TF has the power to amplify thrombin generation once the coagulation cascade is already initiated by surface-bound TF. TF(p) concentrations as low as 0.01 nM were found to have a significant impact on total thrombin generation.
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis St, Suite 9F, Boston, MA, 02115, USA.|Wyss Institute of Biologically Inspired Engineering of Harvard University, Boston, MA, 02215, USA.|Harvard-MIT Division of Health Sciences Technology, Cambridge, MA, 02139, USA.
authors.forename: E Victoria
authors.initials: EV
authors.lastname: Dydek
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis St, Suite 9F, Boston, MA, 02115, USA. echaikof@bidmc.harvard.edu.|Wyss Institute of Biologically Inspired Engineering of Harvard University, Boston, MA, 02215, USA. echaikof@bidmc.harvard.edu.|Harvard-MIT Division of Health Sciences Technology, Cambridge, MA, 02139, USA. echaikof@bidmc.harvard.edu.
authors.forename: Elliot L
authors.initials: EL
authors.lastname: Chaikof
mesh_terms: D003198:Computer Simulation; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D020342:Finite Element Analysis; D006493:Heparin / Q000378:metabolism*; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism*; D013917:Thrombin / Q000378:metabolism*; D013925:Thromboplastin / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; D006493:Heparin; D013925:Thromboplastin; D013917:Thrombin; D003546:Cysteine Endopeptidases; C030910:cancer procoagulant
keywords: Anti-thrombogenic surface; Circulating tissue factor; Numerical model; Surface induced thrombin generation