title: Arterial thrombosis is accelerated in mice deficient in histidine-rich glycoprotein.
abstract: Factor (F) XII, a key component of the contact system, triggers clotting via the intrinsic pathway, and is implicated in propagating thrombosis. Although nucleic acids are potent activators, it is unclear how the contact system is regulated to prevent uncontrolled clotting. Previously, we showed that histidine-rich glycoprotein (HRG) binds FXIIa and attenuates its capacity to trigger coagulation. To investigate the role of HRG as a regulator of the intrinsic pathway, we compared RNA- and DNA-induced thrombin generation in plasma from HRG-deficient and wild-type mice. Thrombin generation was enhanced in plasma from HRG-deficient mice, and accelerated clotting was restored to normal with HRG reconstitution. Although blood loss after tail tip amputation was similar in HRG-deficient and wild-type mice, carotid artery occlusion after FeCl3 injury was accelerated in HRG-deficient mice, and HRG administration abrogated this effect. To confirm that HRG modulates the contact system, we used DNase, RNase, and antisense oligonucleotides to characterize the FeCl3 model. Whereas DNase or FVII knockdown had no effect, carotid occlusion was abrogated with RNase or FXII knockdown, confirming that FeCl3-induced thrombosis is triggered by RNA in a FXII-dependent fashion. Therefore, in a nucleic acid-driven model, HRG inhibits thrombosis by modulating the intrinsic pathway of coagulation.
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, Department of Medical Sciences.
authors.forename: Trang T
authors.initials: TT
authors.lastname: Vu
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, Department of Medicine, and.
authors.forename: Ji
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, Department of Medicine, and.
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Leslie
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, Department of Medicine, and.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Stafford
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, Department of Medicine, and.
authors.forename: James C
authors.initials: JC
authors.lastname: Fredenburgh
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, Department of Medical Sciences.
authors.forename: Ran
authors.initials: R
authors.lastname: Ni
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, Department of Medicine, and.
authors.forename: Shengjun
authors.initials: S
authors.lastname: Qiao
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, Department of Medical Sciences.
authors.forename: Nima
authors.initials: N
authors.lastname: Vaezzadeh
authors.affiliation: Helmholtz-Institute for Biomedical Engineering, Biointerface Laboratory, Rheinisch-Westfälische Technische Hochschule Aachen (RWTH) Aachen University, Aachen, Germany; and.
authors.forename: Willi
authors.initials: W
authors.lastname: Jahnen-Dechent
authors.affiliation: Isis Pharmaceuticals, Inc., Carlsbad, CA.
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, Department of Medical Sciences, Department of Medicine, and.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Gross
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, Department of Medical Sciences, Department of Medicine, and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada;
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Weitz
mesh_terms: D000818:Animals; D001777:Blood Coagulation; D002712:Chlorides; D005174:Factor XII / Q000235:genetics / Q000378:metabolism; D005260:Female; D005290:Ferric Compounds; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D006487:Hemostasis; D051379:Mice; D008810:Mice, Inbred C57BL; D011506:Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism; D013927:Thrombosis / Q000097:blood* / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D000099053:Histidine-Rich Glycoprotein
chemical_list: D002712:Chlorides; D005290:Ferric Compounds; D011506:Proteins; D000099053:Histidine-Rich Glycoprotein; D005174:Factor XII; D013917:Thrombin; C024555:ferric chloride