Inactivation of Factor XIa by Plasma Protease Inhibitors: PREDOMINANT ROLE OF α₁-PROTEASE INHIBITOR AND PROTECTIVE EFFECT OF HIGH MOLECULAR WEIGHT KININOGEN

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Abstract

Factor XIa is a plasma protease that, by activating Factor IX, plays an important role in the early phase of the intrinsic pathway of blood coagulation. Four plasma protease inhibitors, α1-protease inhibitor, antithrombin III, C1-inhibitor, and α2-plasmin inhibitor, have been reported to inactivate human Factor XIa, but their quantitative contribution to the inactivation of Factor XIa in plasma has not been fully assessed. Using purified systems, we observed that the second-order rate constants for the reaction of Factor XIa with α1-protease inhibitor, antithrombin III, and CI-inhibitor were 4.08, 10, and 14.6 M−1 min−1 × 103, respectively. The pseudo-first-order rate constants, at plasma concentration of the inhibitors, were 1.86 × 10−1, 4.68 × 10−2, and 2.4 × 10−2 min−1, respectively. These kinetic data predict that α1-protease inhibitor should account for 68%, antithrombin III for 16%, and C1-inhibitor and the equipotent α2-plasmin inhibitor each for 8% of the total inhibitory activity of plasma against Factor XIa. The rate of inactivation of Factor XIa in various plasma samples specifically deficient in inhibitors was consistent with these predictions.

Authors

Cheryl F. Scott, Marc Schapira, Harold L. James, Allen B. Cohen, Robert W. Colman