Positive feedback of FXI activation by thrombin regulates blood clot growth

Monday, October 24, 2011 — Poster Session I
Noon – 2:00 p.m.	Natcher Conference Center	FDA/CBER	BIOPHY-11

Authors

• AM Shibeko
• WW Li
• MV Ovanesov

Abstract

Activation of factor XI (FXI) by thrombin is important for the propagation phase of thrombin generation in the Tissue Factor (TF) coagulation pathway. Most of the thrombin is generated after clot formation, which brings into question the physiological importance of the propagation phase. We investigated the relationship between thrombin generation (TG), fibrin generation (FG), and clot size growth. TG and FG were monitored in contact-inhibited FXI-deficient plasma mixed with FXI, lipids, fluorogenic thrombin substrate, and TF. FXI had a dose-dependent effect on TG. Clot time, rate of FG, and the amount of thrombin were insensitive to FXI. Therefore, FXI-dependent thrombin generation in plasma mixed with TF occurs after clot formation. Growth of clot from the surface of immobilized TF was studied under light scattering and fluorescence video-microscope. Clot growth rate was proportional to the concentration of FXI. To estimate the location of thrombin activity, we calculated spatio-temporal distributions of FG rate. Fibrin-forming activity was localized to the edge of the clot while in FXI-deficient plasma FG rate was localized to the site of TF exposure. The results indicate that FXI promotes the growth of clot size through the generation of thrombin at the clot/plasma interface.

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