title: A Mathematical Model of Venous Thrombosis Initiation.
abstract: We present a mathematical model for the initiation of venous thrombosis (VT) due to slow flow and the consequent activation of the endothelial cells (ECs) lining the vein, in the absence of overt mechanical disruption of the EC layer. It includes all reactions of the tissue factor (TF) pathway of coagulation through fibrin formation, incorporates the accumulation of blood cells on activated ECs, accounts for the flow-mediated delivery and removal of coagulation proteins and blood cells from the locus of the reactions, and accounts for the activity of major inhibitors including heparan-sulfate-accelerated antithrombin and activated protein C. The model reveals that the occurrence of robust thrombin generation (a thrombin burst) depends in a threshold manner on the density of TF on the activated ECs and on the concentration of thrombomodulin and the degree of heparan-sulfate accelerated antithrombin activity on those cells. Small changes in any of these in appropriate narrow ranges switches the response between "no burst" and "burst." The model predicts synergies among the inhibitors, both in terms of each inhibitor's multiple targets, and in terms of interactions between the different inhibitors. The model strongly suggests that the rate and extent of accumulation of activated monocytes, platelets, and MPs that can support the coagulation reactions has a powerful influence on whether a thrombin burst occurs and the thrombin response when it does. The slow rate of accumulation of cells supporting coagulation is one reason that the progress of VT is so much slower than that of arterial thrombosis initiated by subendothelial exposure.
authors.affiliation: Department of Mathematics, University of Utah, Salt Lake City, Utah.
authors.forename: Priscilla
authors.initials: P
authors.lastname: Elizondo
authors.affiliation: Department of Mathematics, University of Utah, Salt Lake City, Utah; Department of Bioengineering, University of Utah, Salt Lake City, Utah. Electronic address: fogelson@math.utah.edu.
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Fogelson
mesh_terms: D001665:Binding Sites; D001777:Blood Coagulation; D007700:Kinetics; D008954:Models, Biological; D013917:Thrombin / Q000096:biosynthesis; D020246:Venous Thrombosis / Q000378:metabolism / Q000503:physiopathology
chemical_list: D013917:Thrombin