Arterial thrombosis is accelerated in mice deficient in histidine-rich glycoprotein

Blood. 2015 Apr 23;125(17):2712-9. doi: 10.1182/blood-2014-11-611319. Epub 2015 Feb 17.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Coagulation*
  • Chlorides
  • Factor XII / genetics
  • Factor XII / metabolism
  • Female
  • Ferric Compounds
  • Gene Deletion
  • Gene Knockdown Techniques
  • Hemostasis
  • Mice
  • Mice, Inbred C57BL
  • Proteins / analysis
  • Proteins / genetics*
  • Proteins / metabolism
  • Thrombin / metabolism
  • Thrombosis / blood*
  • Thrombosis / chemically induced
  • Thrombosis / genetics*
  • Thrombosis / metabolism


  • Chlorides
  • Ferric Compounds
  • Proteins
  • histidine-rich proteins
  • Factor XII
  • Thrombin
  • ferric chloride