Modeling the role of platelet-released polyphosphates in tissue factor-initiated coagulation under flow.

BACKGROUND

Activated platelets release polyphosphate (polyP), a linear polymer of inorganic phosphate residues, from dense granules. Experiments performed under no-flow conditions show that polyP alters the kinetics of tissue factor (TF) pathway reactions, accelerating factor XI (FXI) activation by thrombin and FV activation by factor Xa and thrombin, and may impact inhibition by tissue factor pathway inhibitor α (TFPIα). How polyP influences this pathway in conjunction with platelet deposition under flow remains understudied.

OBJECTIVES

This study aimed to investigate how polyP-mediated acceleration of FV and FXI activation modulates thrombin generation under flow in TF-initiated coagulation.

METHODS

We extended a previously validated mathematical model of platelet deposition and coagulation under flow to examine polyP-mediated effects after a small vascular injury during intravascular clotting. Simulations varied the surface density of TF exposed, wall shear rate, and plasma TFPIα concentration.

RESULTS

Even without direct interaction between polyP and TFPIα in the model, thrombin generation is much less sensitive to TFPIα concentration with polyP, in a TF-dependent manner. Thrombin concentrations are much more robust across the range of physiological shear rates with polyP than without. Incompletely known accelerations by polyP strongly impact relative contributions of accelerations of FV and FXI activations. PolyP shifts the threshold TF density for a thrombin burst to lower TF densities and shortens the lag time to thrombin generation.

CONCLUSIONS

We identify polyP's effects on blood coagulation beyond acceleration of FV and FXI activation: polyP can produce experimentally-observed TFPIα insensitivity without directly interacting with TFPIα and can improve the robustness of thrombin generation across shear rates.