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. 2014 Aug;34(8):1674-80.
doi: 10.1161/ATVBAHA.114.303315. Epub 2014 May 22.

Factor XII regulates the pathological process of thrombus formation on ruptured plaques

Marijke J E Kuijpers  1 , Paola E J van der Meijden  1 , Marion A H Feijge  1 , Nadine J A Mattheij  1 , Frauke May  1 , José Govers-Riemslag  1 , Joost C M Meijers  1 , Johan W M Heemskerk  1 , Thomas Renné  1 , Judith M E M Cosemans  2
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Factor XII regulates the pathological process of thrombus formation on ruptured plaques

Marijke J E Kuijpers et al. Arterioscler Thromb Vasc Biol. 2014 Aug.

Abstract

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 thrombi and fibrin particularly in luminal-exposed thrombus areas.

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.

Keywords: blood coagulation; blood platelets; factor XII; fibrin; plaque rupture; thrombus; tissue factor.

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Comment in

  • New targets for atherothrombosis.
    Mackman N. Mackman N. Arterioscler Thromb Vasc Biol. 2014 Aug;34(8):1607-8. doi: 10.1161/ATVBAHA.114.304005. Arterioscler Thromb Vasc Biol. 2014. PMID: 25031326 Free PMC article. No abstract available.

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