Factor XII Regulates the Pathological Process of Thrombus Formation on Ruptured Plaques

TY - JOUR

T1 - Factor XII Regulates the Pathological Process of Thrombus Formation on Ruptured Plaques

AU - Kuijpers, Marijke J E

AU - van der Meijden, Paola E J

AU - Feijge, Marion A H

AU - Mattheij, Nadine J A

AU - May, Frauke

AU - Govers-Riemslag, José

AU - Meijers, Joost C M

AU - Heemskerk, Johan W M

AU - Renné, Thomas

AU - Cosemans, Judith M E M

N1 - © 2014 American Heart Association, Inc.

PY - 2014/8

Y1 - 2014/8

N2 - OBJECTIVE: Atherothrombosis is the main cause of myocardial infarction and ischemic stroke. Although the extrinsic (tissue factor-factor VIIa [FVIIa]) pathway is considered as a major trigger of coagulation in atherothrombosis, the role of the intrinsic coagulation pathway via coagulation FXII herein is unknown. Here, we studied the roles of the extrinsic and intrinsic coagulation pathways in thrombus formation on atherosclerotic plaques both in vivo and ex vivo.APPROACH AND RESULTS: Plaque rupture after ultrasound treatment evoked immediate formation of subocclusive thrombi in the carotid arteries of Apoe(-/-) mice, which became unstable in the presence of structurally different FXIIa inhibitors. In contrast, inhibition of FVIIa reduced thrombus size at a more initial stage without affecting embolization. Genetic deficiency in FXII (human and mouse) or FXI (mouse) reduced ex vivo whole-blood thrombus and fibrin formation on immobilized plaque homogenates. Localization studies by confocal microscopy indicated that FXIIa bound to fibrin particularly in thrombus areas that were prone to embolization.CONCLUSIONS: The FVIIa- and FXIIa-triggered coagulation pathways have distinct but complementary roles in atherothrombus formation. The tissue factor-FVIIa pathway contributes to initial thrombus buildup, whereas FXIIa bound to thrombi ensures thrombus stability.

AB - OBJECTIVE: Atherothrombosis is the main cause of myocardial infarction and ischemic stroke. Although the extrinsic (tissue factor-factor VIIa [FVIIa]) pathway is considered as a major trigger of coagulation in atherothrombosis, the role of the intrinsic coagulation pathway via coagulation FXII herein is unknown. Here, we studied the roles of the extrinsic and intrinsic coagulation pathways in thrombus formation on atherosclerotic plaques both in vivo and ex vivo.APPROACH AND RESULTS: Plaque rupture after ultrasound treatment evoked immediate formation of subocclusive thrombi in the carotid arteries of Apoe(-/-) mice, which became unstable in the presence of structurally different FXIIa inhibitors. In contrast, inhibition of FVIIa reduced thrombus size at a more initial stage without affecting embolization. Genetic deficiency in FXII (human and mouse) or FXI (mouse) reduced ex vivo whole-blood thrombus and fibrin formation on immobilized plaque homogenates. Localization studies by confocal microscopy indicated that FXIIa bound to fibrin particularly in thrombus areas that were prone to embolization.CONCLUSIONS: The FVIIa- and FXIIa-triggered coagulation pathways have distinct but complementary roles in atherothrombus formation. The tissue factor-FVIIa pathway contributes to initial thrombus buildup, whereas FXIIa bound to thrombi ensures thrombus stability.

U2 - 10.1161/ATVBAHA.114.303315

DO - 10.1161/ATVBAHA.114.303315

M3 - SCORING: Journal article

C2 - 24855058

VL - 34

SP - 1674

EP - 1680

JO - ARTERIOSCL THROM VAS

JF - ARTERIOSCL THROM VAS

SN - 1079-5642

IS - 8

ER -