title: Factor XII regulates the pathological process of thrombus formation on ruptured plaques.
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.
  
  
  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.
authors.affiliation: From the Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (M.J.E.K., P.E.J.v.d.M., M.A.H.F., N.J.A.M., J.G.-R., J.W.M.H., J.M.E.M.C.); CSL Behring GmbH, Marburg, Germany (F.M.); Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (J.C.M.M.); Department of Plasma Proteins, Sanquin, Amsterdam, The Netherlands (J.C.M.M.); Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden (T.R.); and Department of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (T.R.).
authors.forename: Marijke J E
authors.initials: MJ
authors.lastname: Kuijpers
authors.affiliation: From the Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (M.J.E.K., P.E.J.v.d.M., M.A.H.F., N.J.A.M., J.G.-R., J.W.M.H., J.M.E.M.C.); CSL Behring GmbH, Marburg, Germany (F.M.); Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (J.C.M.M.); Department of Plasma Proteins, Sanquin, Amsterdam, The Netherlands (J.C.M.M.); Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden (T.R.); and Department of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (T.R.).
authors.forename: Paola E J
authors.initials: PE
authors.lastname: van der Meijden
authors.affiliation: From the Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (M.J.E.K., P.E.J.v.d.M., M.A.H.F., N.J.A.M., J.G.-R., J.W.M.H., J.M.E.M.C.); CSL Behring GmbH, Marburg, Germany (F.M.); Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (J.C.M.M.); Department of Plasma Proteins, Sanquin, Amsterdam, The Netherlands (J.C.M.M.); Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden (T.R.); and Department of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (T.R.).
authors.forename: Marion A H
authors.initials: MA
authors.lastname: Feijge
authors.affiliation: From the Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (M.J.E.K., P.E.J.v.d.M., M.A.H.F., N.J.A.M., J.G.-R., J.W.M.H., J.M.E.M.C.); CSL Behring GmbH, Marburg, Germany (F.M.); Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (J.C.M.M.); Department of Plasma Proteins, Sanquin, Amsterdam, The Netherlands (J.C.M.M.); Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden (T.R.); and Department of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (T.R.).
authors.forename: Nadine J A
authors.initials: NJ
authors.lastname: Mattheij
authors.affiliation: From the Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (M.J.E.K., P.E.J.v.d.M., M.A.H.F., N.J.A.M., J.G.-R., J.W.M.H., J.M.E.M.C.); CSL Behring GmbH, Marburg, Germany (F.M.); Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (J.C.M.M.); Department of Plasma Proteins, Sanquin, Amsterdam, The Netherlands (J.C.M.M.); Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden (T.R.); and Department of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (T.R.).
authors.forename: Frauke
authors.initials: F
authors.lastname: May
authors.affiliation: From the Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (M.J.E.K., P.E.J.v.d.M., M.A.H.F., N.J.A.M., J.G.-R., J.W.M.H., J.M.E.M.C.); CSL Behring GmbH, Marburg, Germany (F.M.); Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (J.C.M.M.); Department of Plasma Proteins, Sanquin, Amsterdam, The Netherlands (J.C.M.M.); Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden (T.R.); and Department of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (T.R.).
authors.forename: José
authors.initials: J
authors.lastname: Govers-Riemslag
authors.affiliation: From the Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (M.J.E.K., P.E.J.v.d.M., M.A.H.F., N.J.A.M., J.G.-R., J.W.M.H., J.M.E.M.C.); CSL Behring GmbH, Marburg, Germany (F.M.); Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (J.C.M.M.); Department of Plasma Proteins, Sanquin, Amsterdam, The Netherlands (J.C.M.M.); Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden (T.R.); and Department of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (T.R.).
authors.forename: Joost C M
authors.initials: JC
authors.lastname: Meijers
authors.affiliation: From the Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (M.J.E.K., P.E.J.v.d.M., M.A.H.F., N.J.A.M., J.G.-R., J.W.M.H., J.M.E.M.C.); CSL Behring GmbH, Marburg, Germany (F.M.); Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (J.C.M.M.); Department of Plasma Proteins, Sanquin, Amsterdam, The Netherlands (J.C.M.M.); Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden (T.R.); and Department of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (T.R.).
authors.forename: Johan W M
authors.initials: JW
authors.lastname: Heemskerk
authors.affiliation: From the Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (M.J.E.K., P.E.J.v.d.M., M.A.H.F., N.J.A.M., J.G.-R., J.W.M.H., J.M.E.M.C.); CSL Behring GmbH, Marburg, Germany (F.M.); Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (J.C.M.M.); Department of Plasma Proteins, Sanquin, Amsterdam, The Netherlands (J.C.M.M.); Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden (T.R.); and Department of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (T.R.).
authors.forename: Thomas
authors.initials: T
authors.lastname: Renné
authors.affiliation: From the Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (M.J.E.K., P.E.J.v.d.M., M.A.H.F., N.J.A.M., J.G.-R., J.W.M.H., J.M.E.M.C.); CSL Behring GmbH, Marburg, Germany (F.M.); Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (J.C.M.M.); Department of Plasma Proteins, Sanquin, Amsterdam, The Netherlands (J.C.M.M.); Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden (T.R.); and Department of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (T.R.). judith.cosemans@maastrichtuniversity.nl.
authors.forename: Judith M E M
authors.initials: JM
authors.lastname: Cosemans
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000473:pathology; D001777:Blood Coagulation; D001792:Blood Platelets / Q000378:metabolism*; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D002340:Carotid Artery Diseases / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000473:pathology; D002791:Cholesterol, Dietary; D004195:Disease Models, Animal; D015942:Factor VIIa / Q000378:metabolism; D005172:Factor XI / Q000378:metabolism; D005174:Factor XII / Q000235:genetics / Q000378:metabolism*; D005175:Factor XII Deficiency / Q000097:blood / Q000235:genetics; D015956:Factor XIIa / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic; D012422:Rupture, Spontaneous; D013925:Thromboplastin / Q000378:metabolism; D013927:Thrombosis / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D013997:Time Factors
chemical_list: D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; D005174:Factor XII; D005172:Factor XI; D013925:Thromboplastin; D015942:Factor VIIa; D015956:Factor XIIa
keywords: blood coagulation; blood platelets; factor XII; fibrin; plaque rupture; thrombus; tissue factor