Histidine-rich glycoprotein binds DNA and RNA and attenuates their capacity to activate the intrinsic coagulation pathway.
When triggered by factor (F) XII and nucleic acids, we showed that thrombosis in HRG-deficient mice is accelerated compared with that in wild-type mice. In this study, we set out to identify the mechanisms by which nucleic acids promote contact activation, and to determine whether HRG attenuates their effects. DNA or RNA addition to human plasma enhances thrombin generation via the intrinsic pathway and shortens the clotting time. Their effect on the clotting time is seven- to 14-fold greater in HRG-deficient plasma than in control plasma. Investigations into the mechanisms of activation reveal that nucleic acids a) promote FXII activation in the presence of prekallikrein- and high molecular weight kininogen (HK), and b) enhance thrombin-mediated FXI activation by 10- to 12-fold. Surface plasmon resonance studies show that DNA and RNA bind FXII, FXIIa, HK, FXI, FXIa and thrombin with high affinity. HRG attenuates DNA- and RNA-mediated FXII activation, and FXI activation by FXIIa or by thrombin, suggesting that HRG down regulates the capacity of DNA and RNA to activate the intrinsic pathway. Therefore, HRG attenuates the procoagulant activity of nucleic acids at multiple levels.
Trang T
TT
Vu
Beverly A
BA
Leslie
Alan R
AR
Stafford
Ji
J
Zhou
James C
JC
Fredenburgh
Jeffrey Weitz, Thrombosis and Atherosclerosis Research Institute, 237 Barton St. E, Hamilton, Ontario L8L 2X2, Canada, Tel.: +1 905 521 2100 ext 40721, Fax: +1 905 575 2646, E-mail: weitzj@taari.ca.
Jeffrey I
JI
Weitz
D001667:Binding, Competitive; D001777:Blood Coagulation; D004247:DNA / Q000097:blood / Q000378:metabolism*; D004789:Enzyme Activation; D015956:Factor XIIa / Q000378:metabolism; D015945:Factor XIa / Q000378:metabolism; D006801:Humans; D019679:Kininogen, High-Molecular-Weight / Q000378:metabolism; D011288:Prekallikrein / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D012313:RNA / Q000097:blood / Q000378:metabolism*; D020349:Surface Plasmon Resonance; D013917:Thrombin / Q000378:metabolism; D014914:Whole Blood Coagulation Time; D000099053:Histidine-Rich Glycoprotein
D019679:Kininogen, High-Molecular-Weight; D011506:Proteins; D000099053:Histidine-Rich Glycoprotein; D012313:RNA; D004247:DNA; D011288:Prekallikrein; D015945:Factor XIa; D015956:Factor XIIa; D013917:Thrombin
Coagulation; DNA; RNA; histidine-rich glycoprotein; intrinsic pathway