title: Histidine-rich glycoprotein binds factor XIIa with high affinity and inhibits contact-initiated coagulation.
abstract: Histidine-rich glycoprotein (HRG) circulates in plasma at a concentration of 2μM and binds plasminogen, fibrinogen, and thrombospondin. Despite these interactions, the physiologic role of HRG is unknown. Previous studies have shown that mice and humans deficient in HRG have shortened plasma clotting times. To better understand this phenomenon, we examined the effect of HRG on clotting tests. HRG prolongs the activated partial thromboplastin time in a concentration-dependent fashion but has no effect on tissue factor-induced clotting, localizing its effect to the contact pathway. Plasma immunodepleted of HRG exhibits a shortened activated partial thromboplastin time that is restored to baseline with HRG replenishment. To explore how HRG affects the contact pathway, we examined its binding to factors XII, XIIa, XI, and XIa. HRG binds factor XIIa with high affinity, an interaction that is enhanced in the presence of Zn²(+), but does not bind factors XII, XI, or XIa. In addition, HRG inhibits autoactivation of factor XII and factor XIIa-mediated activation of factor XI. These results suggest that, by binding to factor XIIa, HRG modulates the intrinsic pathway of coagulation, particularly in the vicinity of a thrombus where platelet release of HRG and Zn²(+) will promote this interaction.
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University and the Thrombosis and Atherosclerosis Research Institute, Hamilton, ON.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: MacQuarrie
authors.forename: Alan R
authors.initials: AR
authors.lastname: Stafford
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Yau
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Leslie
authors.forename: Trang T
authors.initials: TT
authors.lastname: Vu
authors.forename: James C
authors.initials: JC
authors.lastname: Fredenburgh
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Weitz
mesh_terms: D001777:Blood Coagulation / Q000502:physiology*; D001780:Blood Coagulation Tests; D005172:Factor XI / Q000378:metabolism; D005174:Factor XII / Q000378:metabolism; D015956:Factor XIIa / Q000378:metabolism*; D015945:Factor XIa / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D007610:Kallikreins / Q000378:metabolism; D011288:Prekallikrein / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D013927:Thrombosis / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism; D000099053:Histidine-Rich Glycoprotein
chemical_list: D011506:Proteins; D000099053:Histidine-Rich Glycoprotein; D005174:Factor XII; D005340:Fibrinogen; D005172:Factor XI; D011288:Prekallikrein; D007610:Kallikreins; D015945:Factor XIa; D015956:Factor XIIa; D015032:Zinc