PB1035 - Mathematical modeling suggests the importance of TFPI-mediated inhibition of platelet-surface bound proteins during coagulation under flow

Background: Our previously-validated mathematical model of platelet deposition and coagulation under flow was extended to include TFPI’s action on platelet-surface-bound proteins.

Aims: To characterize the effectiveness of TPFI-mediated inhibition of platelet-bound FXa, partially-activated FVa, and early prothrombinase on the timing and strength of thrombin production.

Methods: Differential equations for the concentrations of new species (e.g., partially-activated factor V) were added to the model and existing equations were modified to reflect new reactions. Simulations were carried out for ranges of tissue factor exposure, flow shear rate, and values of the new kinetic rates and plasma concentrations of new species.

Results: The new model is sensitive to TFPI levels; thrombin production can be largely prevented by sufficiently high TFPI concentrations. The sensitivity is due entirely to reactions on the platelet surface and not to TPFI’s inhibition of TF:VIIa or fluid-phase FXa. The new TPFI reactions increase the threshold level of TF needed to elicit a strong thrombin response under flow, and they delayed the onset of strong thrombin production, but had little effect on the eventual thrombin concentration reached with a strong response. The inhibitory effect of TPFI binding to platelet-bound FXa was greater than that of its binding to platelet-bound partially-activated FV, and the two inhibitory effects were additive. The model includes platelet release of a mixture of FV and partially-activated FV. Increasing the fraction of partially-activated FV released accelerated thrombin production.

Conclusion(s): The model suggests that for coagulation under flow, the dominant effects of TFPI come from its inhibition of platelet-bound coagulation factors, and the effects are a change in TF sensitivity and a delay in thrombin production.