Thrombogenic potential of picomolar coagulation factor XIa is mediated by thrombin wave propagation.

Inhibitors of coagulation factor (F) XIa are currently investigated as potential anticoagulant therapies. We hypothesized that circulating FXIa may be a potential target for these therapies. Using previous analyses of FXIa impurity in immune globulin products involved in thrombotic adverse events, we estimated that picomolar levels of FXIa can be thrombogenic. In an in vitro clot growth assay, 0.1-3 pM of FXIa did not, by itself, activate clotting, but increased the size of growing clots. Spatio-temporal reconstruction of thrombin activity inside the clot revealed that FXIa's effect was limited to the clot-plasma interface, where FXIa produced a taller than normal wave of thrombin. Factor-depleted plasmas and a panel of selective anti-FXIa antibodies showed that exogenous FXIa effects are (1) blocked by the anti-FXIa antibodies, (2) independent from FXI activation inside the clot, and (3) larger than the contribution of in situ FXIa. In a thrombin generation (TG) assay, picomolar FXIa did not initiate TG, but rather promoted TG triggered with tissue factor or thrombin, suggesting that the effect of FXIa on the thrombin wave is mediated by elevation of thrombin-triggered TG. In flowing bovine blood, low doses of human FXIa did not initiate clotting, but increased the size of stenosis-triggered thrombi. FXIa injection in mice enhanced TG in plasma for at least 6 hours ex vivo, confirming persistence of circulating FXIa. Our findings suggest that picomolar levels of circulating FXIa may not be able to start thrombosis but can facilitate thrombus growth through facilitation of TG inside the clot.