Background: As a component of the kallikrein-kinin system, factor XIIa (FXIIa) contributes to bradykinin generation by converting prekallikrein to kallikrein. Kallikrein, in turn, cleaves the precursor FXII after Arg353, forming FXIIa. FXII variants with Lys/Arg substitutions for Thr309 are cleaved by several proteases after Lys/Arg309, forming truncated FXII (Thr310-Ser596) that is activated by kallikrein more rapidly than full-length FXII. This explains why patients with Thr309Arg/Lys are prone to bradykinin-mediated soft tissue swelling (angioedema). Plasmin also activates FXII by cleavage after Arg353, although the reaction is relatively slow. Angioedema occasionally occurs in patients receiving fibrinolytic therapy. While this may reflect plasmin cleavage of FXII after Arg353, proteolytic FXII truncation, even in the absence of Thr309Arg/Lys, is also possible.

Aims: To study the effects of plasmin on FXII structure and activation.

Methods: FXII cleavage and activity were assessed with western blots and chromogenic substrate assays.

Results: Plasmin cleaves FXII at several locations. Cleavage after Arg353 appears to be a relatively minor event. Major cleavage events occurred in the FXII proline-rich region after Arg334, Arg326 and Arg291. Truncated recombinant FXII lacking sequence N-terminal to Arg334, Arg326 and Arg291 are activated by kallikrein ~15-times faster than full-length FXII. When added to plasma, truncated species, but not full-length FXII, induced rapid cleavage of high-molecular-weight kininogen in a manner not dependent on a surface/polyanion to induce contact activation.

Conclusions: In addition to converting FXII to FXIIa by cleavage after Arg353, plasmin may cleave FXII at other sites, creating truncated FXII forms that are activated by kallikrein more rapidly than full-length FXII. This observation may be relevant to the angioedema that occurs in occasional patients treated with fibrinolytic therapy to alleviate blood vessel obstruction. If this mechanism is relevant to angioedema, it remains to be determined why it occurs in some patients, but not others.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/effects-of-plasmin-on-factor-xii-structure-and-activation/