title: Factor XI regulates pathological thrombus formation on acutely ruptured atherosclerotic plaques.
abstract: OBJECTIVE
  Coagulation factor XI is proposed as therapeutic target for anticoagulation. However, it is still unclear whether the antithrombotic properties of factor XI inhibitors influence atherosclerotic disease and atherothrombosis. Our aim is to investigate whether factor XI antisense oligonucleotides could prevent thrombus formation on acutely ruptured atherosclerotic plaques.
  
  
  RESULTS
  Atherosclerotic plaques in the carotid arteries of Apoe(-/-) mice were acutely ruptured using ultrasound. The subsequent thrombus formation was visualized and quantified by intravital microscopy and immunohistochemistry. Mice were pretreated with either factor XI antisense or nonsense oligonucleotides (50 mg/kg) to lower factor XI plasma levels. A tail bleeding assay was used to determine the safety. On plaque rupture, initial platelet adhesion and platelet plug formation were not impaired in animals treated with factor XI antisense oligonucleotides. However, the ensuing thrombus formation and fibrin deposition were significantly lower after 5 to 10 minutes (P<0.05) in factor XI antisense oligonucleotide-treated animals without inducing a bleeding tendency. Furthermore, thrombi from antisense-treated animals were less stable than thrombi from placebo-treated animals. Moreover, macrophage infiltration and collagen deposition were lower in the carotid arteries of factor XI antisense-treated animals. No neutrophils were present.
  
  
  CONCLUSIONS
  Factor XI antisense oligonucleotides safely prevent thrombus formation on acutely ruptured atherosclerotic plaques in mice. Furthermore, perturbed carotid arteries from factor XI antisense-treated animals show a less severe inflammatory response.
authors.affiliation: From the Departments of Experimental Vascular Medicine (M.L.v.M., V.L.K., J.C.M.M.) and Pathology (J.J.T.H.R.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (M.J.E.K., J.W.M.H.); Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc, Carlsbad, CA (S.B., B.P.M.); and Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands (J.C.M.M.).
authors.forename: Maurits L
authors.initials: ML
authors.lastname: van Montfoort
authors.affiliation: From the Departments of Experimental Vascular Medicine (M.L.v.M., V.L.K., J.C.M.M.) and Pathology (J.J.T.H.R.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (M.J.E.K., J.W.M.H.); Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc, Carlsbad, CA (S.B., B.P.M.); and Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands (J.C.M.M.).
authors.forename: Marijke J E
authors.initials: MJ
authors.lastname: Kuijpers
authors.affiliation: From the Departments of Experimental Vascular Medicine (M.L.v.M., V.L.K., J.C.M.M.) and Pathology (J.J.T.H.R.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (M.J.E.K., J.W.M.H.); Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc, Carlsbad, CA (S.B., B.P.M.); and Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands (J.C.M.M.).
authors.forename: Véronique L
authors.initials: VL
authors.lastname: Knaup
authors.affiliation: From the Departments of Experimental Vascular Medicine (M.L.v.M., V.L.K., J.C.M.M.) and Pathology (J.J.T.H.R.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (M.J.E.K., J.W.M.H.); Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc, Carlsbad, CA (S.B., B.P.M.); and Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands (J.C.M.M.).
authors.forename: Sanjay
authors.initials: S
authors.lastname: Bhanot
authors.affiliation: From the Departments of Experimental Vascular Medicine (M.L.v.M., V.L.K., J.C.M.M.) and Pathology (J.J.T.H.R.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (M.J.E.K., J.W.M.H.); Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc, Carlsbad, CA (S.B., B.P.M.); and Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands (J.C.M.M.).
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
authors.affiliation: From the Departments of Experimental Vascular Medicine (M.L.v.M., V.L.K., J.C.M.M.) and Pathology (J.J.T.H.R.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (M.J.E.K., J.W.M.H.); Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc, Carlsbad, CA (S.B., B.P.M.); and Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands (J.C.M.M.).
authors.forename: Joris J T H
authors.initials: JJ
authors.lastname: Roelofs
authors.affiliation: From the Departments of Experimental Vascular Medicine (M.L.v.M., V.L.K., J.C.M.M.) and Pathology (J.J.T.H.R.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (M.J.E.K., J.W.M.H.); Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc, Carlsbad, CA (S.B., B.P.M.); and Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands (J.C.M.M.).
authors.forename: Johan W M
authors.initials: JW
authors.lastname: Heemskerk
authors.affiliation: From the Departments of Experimental Vascular Medicine (M.L.v.M., V.L.K., J.C.M.M.) and Pathology (J.J.T.H.R.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (M.J.E.K., J.W.M.H.); Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc, Carlsbad, CA (S.B., B.P.M.); and Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands (J.C.M.M.). j.c.meijers@amc.uva.nl.
authors.forename: Joost C M
authors.initials: JC
authors.lastname: Meijers
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D001777:Blood Coagulation; D001792:Blood Platelets / Q000378:metabolism*; D002339:Carotid Arteries / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002340:Carotid Artery Diseases / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002791:Cholesterol, Dietary; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005172:Factor XI / Q000235:genetics / Q000378:metabolism*; D005337:Fibrin / Q000378:metabolism; D007249:Inflammation / Q000097:blood / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage; D058226:Plaque, Atherosclerotic; D010973:Platelet Adhesiveness; D010974:Platelet Aggregation; D012422:Rupture, Spontaneous; D013927:Thrombosis / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D013997:Time Factors
chemical_list: D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; D016376:Oligonucleotides, Antisense; D005337:Fibrin; D003094:Collagen; D005172:Factor XI
keywords: atherosclerosis; blood coagulation; factor XI; thrombosis