OC 79.2 - Differential impact of factor XII, factor XI and prekallikrein deficiency on thrombosis: a pro-thrombotic vascular action of bradykinin

Background: Factor XII (FXII) initiates the plasma contact system that triggers the intrinsic coagulation pathway and the kallikrein-kinin pathway via factor XI (FXI) and plasma prekallikrein (PK), respectively. A comprehensive head-to-head comparison of the three proteases in arterial thrombosis is missing, and the underlying mechanism is not fully understood.

Aims: To examine the relative importance of FXII, FXI and PK in thrombosis and elucidate the related mechanism.

Methods: Mice deficient in FXII (F12-/-), FXI (F11-/-) and PK (Klkb1-/-) were produced and compared in two distinct thrombosis models. A role of bradykinin in thrombosis was assessed in vivo following contact activation or its level modulation, and its action on platelet-endothelium interactions was examined in vitro.

Results: In ferric chloride induced carotid artery thrombosis, all of the wildtype mice formed occlusive thrombi, and the occlusion rate was reduced to 0, 4.8%, 27.3% in F12-/-, F11-/- and Klkb1-/- mice, respectively. In photochemical-induced cremaster arteriolar thrombosis, occlusion time (sec) prolonged to 226.1±60.4 (mean±SEM), 123.8±32.0 and 87.8±25.3 in F12-/-, F11-/- and Klkb1-/- mice, respectively, largely exceeding that of wildtype mice (38.3±12.1). A discordance was observed between in vivo thrombotic effects of the proteases and their roles for ex vivo coagulation, which ranked FXII≈FXI>PK as assayed by thromboelastography and activated partial thromboplastin time. Activation of FXII promoted thrombosis in wildtype and Klkb1-/- mice, and impressively, it also accelerated thrombosis in F11-/- mice, increasing activated PK activity and plasma bradykinin formation. Infusion of bradykinin and blockade of degradation of endogenous bradykinin increased platelet-endothelium adhesion and promoted thrombotic occlusions, which involved bradykinin mediated endothelial cell-release of platelet activating factor, rather than direct activation of platelets by bradykinin.

Conclusion(s): FXII and FXI are critical in experimental thrombosis relative to PK, while PK-bradykinin axis contributes to thrombosis in an endothelium-dependent manner.