INACTIVATION OF FACTOR-XIA IN-VIVO - STUDIES IN CHIMPANZEES AND IN HUMANS

C1-inhibitor (C1Inh), antithrombin III (ATIII), alpha(1)-antitrypsin ( a1AT), and alpha(2)-antiplasmin (a2AP) are known inhibitors of factor XIa (FXIa). However, their precise contribution to FXIa inactivation i n vive is not known. We investigated FXIa inactivation in chimpanzees and assessed the contribution of these inhibitors to FXIa inactivation in patients with presumed FXI activation. Chimpanzees were infused wi th FXIa and the various FXIa-FXIa inhibitor complexes formed were meas ured. Most of FXIa was complexed to C1Inh (68%), followed by a2AP (13% ), a1AT (10%), and ATIII (9%). Analysis of the plasma elimination kine tics revealed a half-life time of clearance (t(1/2)) for the FXIa-FXIa inhibitor complexes of 95 to 104 min, except for FXIa-a1AT, which had a t(1/2) of 349 min. Due to this long t(1/2), FXIa-a1AT complexes wer e predicted to show the highest levels in plasma samples from patients with activation of FXI. This was indeed shown in patients with dissem inated intravascular coagulation, recent myocardial infarction or unst able angina pectoris. We conclude from this study that in vive C1Inh i s the predominant inhibitor of FXIa, but that FXIa-a1AT complexes due to their relatively long t(1/2) may be the best parameter to assess FX I activation in clinical samples.