Targeting FXI or FXII limits thrombotic complications and prolongs ECMO circuit life (citrate/calcium cohort). (A) A higher dose of FXII ASO (30 mg/kg) decreased circulating FXII activity to ∼2% of normal, a level significantly lower than that achieved with 20 mg/kg (B). (C) A separate cohort of rabbits was treated with an FXI-specific ASO resulting in FXI activity levels < 5% of baseline at the time of ECMO initiation. (D-F) Shown are the results of experiments where donor rabbit blood was anticoagulated with citrate, followed by normalization of plasma calcium. (D) Depletion of either FXI or FXII significantly prolonged the life of a revised ECMO circuit using 2 micro-oxygenators placed in parallel. (E) Shown are the pressures across the oxygenators as a function of time for each animal. Note that all 3 control rabbits experienced significant pressure spikes across the oxygenators just before circuit failure, whereas oxygenator pressure remained relatively stable in the heparin-treated animals, as well as the FXII- and FXI-depleted animals. (F) Thrombi were readily evident on all the oxygenators used for the control animals, whereas none of the oxygenators used in heparin, FXI ASO-, or FXII ASO-treated rabbits had evidence of visible thrombi.