Abstract 15197: Differential Impact of Factor XII, Factor XI and Prekallikrein Deficiency on Thrombosis: A Pro-Thrombotic Vascular Action of Bradykinin

Abstract

Objective: 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. The importance of the contact system for thrombosis sparing hemostasis is well established, however a comprehensive head-to-head comparison of the three proteases in arterial thrombosis is missing. Approach and Results: We produced mice deficient in FXII ( F12 -/- ), FXI ( F11 -/- ) and PK ( Klkb1 -/- ) and compared them in two distinct thrombosis models. While all (100%) of WT mice formed occlusive thrombi upon 30% ferric chloride challenge, carotid artery occlusion was reduced to 0, 4.8, 27.3 % in F12 -/- , F11 -/- and Klkb1 -/- mice (n=14-22), respectively. Upon photochemical-induced cremaster arteriolar thrombosis, occlusion time (s) prolonged to 226.1±60.4, 123.8±32.0 and 87.8±25.3 (mean±SEM, n=10-15) respectively in F12 -/- , F11 -/- and Klkb1 -/- mice, largely exceeding WT levels (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 WT 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: FXII, FXI and PK differentially mediate experimental thrombosis in vivo and FXII/FXI appear as superior targets for thrombosis as compared to PK. PK- bradykinin axis activated by FXII contributes to thrombosis in vivo .