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 (TFp) was investigated and compared to that of surface-bound tissue factor (TFs). 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. TFp concentrations as low as 0.01 nM were found to have a significant impact on total thrombin generation.

Simulated thrombin responses in venous valves

“…We have previously demonstrated that shear rate influences the TF surface density required to generate a threshold concentration of thrombin that is sufficient to propagate the cascade. 18, 22 This observation supports the notion that mass transport has an important impact on the sensitivity of a given hemodynamic environment to generate thrombin induced by surface-bound TF. Each of the TF positions considered in these studies experiences different mass transport conditions, as a consequence of the large vortex near the valve opening (Figure 1D).…”

“…22 In short, the presence of surface-bound TF initiates the cascade by reversibly binding to activated factor VIIa, forming extrinsic tenase. Extrinsic tenase activates factor X and IX, where activated factor Xa activates factors VII and V. Surface species prothrombinase is formed by the binding of activated factors Xa and Va. Prothrombinase, in turn, activates factors VII, as well as factor II (prothrombin) producing thrombin.…”

“…As an approximation, the surface density of surface bound TM was set at 1000 fmol/cm 2 , as prior studies have demonstrated that at this level the generation of activated protein C is transport limited. 18, 22 This estimation ensures that the inhibition of thrombin formation will not be limited by TM expression. A range of surface bound TF densities were considered from ~0.1 to 2 fmol/cm 2 .…”

“…12–18 While some of these numerical models include blood flow, none have considered disturbed flow, which is likely a critical component in the development of VTE, as venous valves induce eddies that both lead to the induction of TF and increase the residence time of locally produced clotting factors. 19–21 In this report, we expand upon a recently described numerical model that highlights the significance of surface reactions 18, 22 through the incorporation of disturbed flow induced by an open venous valve in the equilibrium phase of the valve cycle. We analyzed the degree and location of thrombin formation with respect to TF position and compare these results to the case of non-disturbed flow, when a valve is not present.…”

Mathematics of Pharmacokinetics and Pharmacodynamics: Diversity of Topics, Models and Methods

“…Heparin upregulates the activity of antithrombin which reduces blood coagulability. In a recent work [30], Dydek and Chaikof equipped a previously developed model for in situ clot growth with the action of heparin. The resulting model is detailed and focuses on the spatio-temporal dynamics of clot growth during heparin treatment.…”