Regulation of clot growth by endogenous FXI zymogen. Diagrams illustrate the 3 experimental conditions to modulate the interaction of FXI with FIX and thrombin. In all experiments, FXI activation by FXIIa is blocked by CTI. Solid black arrows illustrate active pathways, and dashed gray arrows indicate inhibited pathways. Zymogens and enzymes are represented by blue and orange ellipses, respectively. (A) Thrombin-mediated activation of FXI is blocked in the absence of FXI (ie, in FXI-deficient plasma). (B) Antibody αFXI-2 inhibits FXI and FXIa. (C) Antibody O1A6 inhibits FXI activation by thrombin and FIX activation by FXIa. (D) Condition A: TG profiles inside the growing clot in FXI-deficient plasma without FXIa. Shown representative of 2 repeats. (E) Condition A + FXIa: TG profiles inside a growing clot in FXI-deficient plasma supplemented with 0.48 pM of FXIa. Shown representative of 2 repeats. (F) Clot-growth rate in healthy normal pooled plasma (NPP; green curve), FXI-deficient plasma with (blue curve) or without (red curve) 0.12 pM FXIa, and in healthy plasma treated with αFXI-2 (light blue curve) or O1A6 (gray curve). The standard deviation of the averaged clot-growth rate is indicated by the colored shades around the curves. Note that the addition of 0.12 pM FXIa to FXI-deficient plasma normalized the clot-growth rate. Shown representative of 2--4 repeats. (G) The average rate of clot growth as a function of FXIa activity. FXIa increased the average clot-growth rate in healthy (green) and FXI-deficient (purple) plasma in a dose-dependent manner. The antibody for FXI and FXIa, αFXI-2, neutralized the effect of FXIa in FXI-deficient plasma (blue triangle) but did not affect clot growth in untreated FXI-deficient plasma (red circle), confirming the specificity of αFXI-2 to FXIa. Shown representative of 1--4 repeats.